Substituted triazinyl amide derivatives and methods of use

ABSTRACT

The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer and angiogenesis-related disease.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/282,977, filed Apr. 11, 2001, which is herebyincorporated by reference.

FIELD OF THE INVENTION

[0002] This invention is in the field of pharmaceutical agents andspecifically relates to compounds, compositions, uses and methods fortreating cancer and angiogenesis-related disorders.

BACKGROUND OF THE INVENTION

[0003] Phosphoryl transferases are a large family of enzymes thattransfer phosphorous-containing groups from one substrate to another.Kinases are a class of enzymes that function in the catalysis ofphosphoryl transfer. The protein kinases constitute the largestsubfamily of structurally related phosphoryl transferases and areresponsible for the control of a wide variety of signal transductionprocesses within the cell. Almost all kinases contain a similar 250-300amino acid catalytic domain. The protein kinases may be categorized intofamilies by the substrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, etc.). Protein kinase sequence motifs havebeen identified that generally correspond to each of these kinasefamilies. Lipid kinases (e.g. PI3K) constitute a separate group ofkinases with structural similarity to protein kinases.

[0004] The “kinase domain” appears in a number of polypeptides whichserve a variety of functions. Such polypeptides include, for example,transmembrane receptors, intracellular receptor associated polypeptides,cytoplasmic located polypeptides, nuclear located polypeptides andsubcellular located polypeptides. The activity of protein kinases can beregulated by a variety of mechanisms. It must be noted, however, that anindividual protein kinase may be regulated by more than one mechanism.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, protein-polynucleotide interactions, ligandbinding, and post-translational modification.

[0005] Protein and lipid kinases regulate many different cell processesincluding, but not limited to, proliferation, growth, differentiation,metabolism, cell cycle events, apoptosis, motility, transcription,translation and other signaling processes, by adding phosphate groups totargets such as proteins or lipids. Phosphorylation events catalyzed bykinases act as molecular on/off switches that can modulate or regulatethe biological function of the target protein. Phosphorylation of targetproteins occurs in response to a variety of extracellular signals(hormones, neurotransmitters, growth and differentiation factors, etc.),cell cycle events, environmental or nutritional stresses, etc. Proteinand lipid kinases can function in signaling pathways to activate orinactivate, or modulate the activity of (either directly or indirectly)the targets. These targets may include, for example, metabolic enzymes,regulatory proteins, receptors, cytoskeletal proteins, ion channels orpumps, or transcription factors. Uncontrolled signaling due to defectivecontrol of protein phosphorylation has been implicated in a number ofdiseases and disease conditions, including, for example, inflammation,cancer, allergy/asthma, disease and conditions of the immune system,disease and conditions of the central nervous system (CNS),cardiovascular disease, dermatology, and angiogenesis.

[0006] Initial interest in protein kinases as pharmacological targetswas stimulated by the findings that many viral oncogenes encodestructurally modified cellular protein kinases with constitutive enzymeactivity. These findings pointed to the potential involvement ofoncogene related protein kinases in human proliferative disorders.Subsequently, deregulated protein kinase activity, resulting from avariety of more subtle mechanisms, has been implicated in thepathophysiology of a number of important human disorders including, forexample, cancer, CNS conditions, and immunologically related diseases.The development of selective protein kinase inhibitors that can blockthe disease pathologies and/or symptoms resulting from aberrant proteinkinase activity has therefore generated much interest.

[0007] Protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processes,maintaining control over cellular function. A partial list of suchkinases includes abl, Atk, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src,CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1,CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2,FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak,KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK,Yes, and Zap70. Inhibition of such kinases has become an importanttherapeutic target.

[0008] Certain diseases are known to be associated with deregulatedangiogenesis, for example ocular neovascularisation, such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,inflammatory disease, such as a rheumatoid or rheumatic inflammatorydisease, especially arthritis (including rheumatoid arthritis), or otherchronic inflammatory disorders, such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias).

[0009] At the center of the network regulating the growth anddifferentiation of the vascular system and its components, both duringembryonic development and normal growth, and in a wide number ofpathological anomalies and diseases, lies the angiogenic factor known asVascular Endothelial Growth Factor” (=VEGF; originally termed 'VascularPermeability Factor”, =VPF), along with its cellular receptors.

[0010] VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein relatedto “Platelet-Derived Growth Factor” (PDGF). It is produced by normalcell lines and tumor cell lines, is an endothelial cell-specificmitogen, shows angiogenic activity in in vivo test systems (e.g. rabbitcornea), is chemotactic for endothelial cells and monocytes, and inducesplasminogen activators in endothelial cells, which are involved in theproteolytic degradation of extracellular matrix during the formation ofcapillaries. A number of isoforms of VEGF are known, which showcomparable biological activity, but differ in the type of cells thatsecrete them and in their heparin-binding capacity. In addition, thereare other members of the VEGF family, such as “Placenta Growth Factor”(PLGF) and VEGF-C.

[0011] VEGF receptors (VEGFR) are transmembranous receptor tyrosinekinases. They are characterized by an extracellular domain with sevenimmunoglobulin-like domains and an intracellular tyrosine kinase domain.Various types of VEGF receptor are known, e.g. VEGFR-1 (also known asflt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

[0012] A large number of human tumors, especially gliomas andcarcinomas, express high levels of VEGF and its receptors. This has ledto the hypothesis that the VEGF released by tumor cells could stimulatethe growth of blood capillaries and the proliferation of tumorendothelium in a paracrine manner and through the improved blood supply,accelerate tumor growth. Increased VEGF expression could explain theoccurrence of cerebral edema in patients with glioma. Direct evidence ofthe role of VEGF as a tumor angiogenesis factor in vivo is shown instudies in which VEGF expression or VEGF activity was inhibited. Thiswas achieved with anti-VEGF antibodies, with dominant-negative VEGFR-2mutants which inhibited signal transduction, and with antisense-VEGF RNAtechniques. All approaches led to a reduction in the growth of gliomacell lines or other tumor cell lines in vivo as a result of inhibitedtumor angiogenesis.

[0013] Angiogenesis is regarded as an absolute prerequisite for tumorswhich grow beyond a diameter of about 1-2 mm; up to this limit, oxygenand nutrients may be supplied to the tumor cells by diffusion. Everytumor, regardless of its origin and its cause, is thus dependent onangiogenesis for its growth after it has reached a certain size.

[0014] Three principal mechanisms play an important part in the activityof angiogenesis inhibitors against tumors: 1) Inhibition of the growthof vessels, especially capillaries, into avascular resting tumors, withthe result that there is no net tumor growth owing to the balance thatis achieved between apoptosis and proliferation; 2) Prevention of themigration of tumor cells owing to the absence of blood flow to and fromtumors; and 3) Inhibition of endothelial cell proliferation, thusavoiding the paracrine growth-stimulating effect exerted on thesurrounding tissue by the endothelial cells which normally line thevessels.

[0015] U.S. Pat. No. 5,215,569, issued Jun. 1, 1993, describessubstituted pyridines as herbicides. WO99/01136 describes substitutedimidazoles as p38 inhibitors. WO00/43373 describes pyrimidinones askinase inhibitors. Shapiro et al. (J. Amer. Chem.Soc., 79, 5064-71(1957)) describe guanamines as potential diuretics. U.S. Pat. No.3,136,816, issued Jun. 9, 1964, describe guanamines as potentialdiuretics. WO99/65909 describes pyrrolopyrimidine compounds as kinaseinhibitors. WO97/19065 describes anilinopyrimidines as kinaseinhibitors. U.S. Pat. No. 2,474,194, issued Jun. 21, 1949, describeguanamines as plastic additives. Swiss patent 261812 describes thepreparation of triazines. British patent 1,390,235 describestrisubstituted triazines as agents for the treatment of the hormonesystem.

[0016] Schipper U.S. Pat. No. 3,226,394, issued Dec. 28, 1965, describesanthranilamides as CNS depressants. Japanese patent JP2000256358describes pyrazole derivatives that block the calcium release-activatedcalcium channel. EP application 9475000, published Oct. 6, 1999,describes compounds as PGE₂ antagonists. PCT publication WO96/41795,published Dec. 27, 1996, describes benzamides as vasopressinantagonists.

[0017] U.S. Pat. No. 5,532,358, issued Jul. 2, 1996, describes thepreparation of2-(cyclopropylamino)-N-(2-methoxy-4-methyl-3-pyridinyl)-3-pyridinecarboxamideas an intermediate for HIV inhibitors. Triazine-substituted amines aredescribed for their aggregating ability (J. Amer. Chem. Soc., 115,905-16 (1993). Substituted imidazolines were tested for theirantidepressant activity in Ind. J. Het. Chem., 2, 129-32 (1992).N-(4-Pyridyl)anthranilic amides were described in Chem Abstr. 97:109837(1981). PCT publication WO99/32477, published Jul. 1, 1999, describesanthranilamides as anti-coagulants. PCT publication WO99/62885,published Dec. 9, 1999, describes 1-(4-aminophenyl)pyrazoles asantiinflammatories. PCT publication WO00/39111, published Jul. 6, 2000,describes amides as factor Xa inhibitors. PCT publication WO00/39117,published Jul. 6, 2000, describes heteroaromatic amides as factor Xainhibitors. PCT publication WO00/27819, published May 18, 2000,describes anthranilic acid amides as VEGF inhibitors. PCT publicationWO00/27820 published May 18, 2000, describes N-aryl anthranilic acidamides as VEGF inhibitors. 7-Chloroquinolinylamines are described inFR2168227 as antiinflammatories.

[0018] However, compounds of the current invention have not beendescribed as inhibitors of angiogenesis such as for the treatment ofcancer.

DESCRIPTION OF THE INVENTION

[0019] A class of compounds useful in treating cancer and angiogenesisis defined by Formula I

[0020] wherein R¹ is selected from phenyl substituted with R^(4a) andoptionally substituted with 1-4 R⁴, and heteroaryl substituted withR^(4a) and optionally substituted with 1-4 R⁴ on each ring;

[0021] preferably phenyl substituted with R4a and optionally substitutedwith 1-3 R⁴, and 5-10 membered heteroaryl substituted with R^(4a) andoptionally substituted with 1-3 R⁴;

[0022] more preferably phenyl ortho-substituted with R^(4a) andoptionally substituted with R⁴; and

[0023] 5-10 membered heteroaryl ortho substituted with R^(4a) andoptionally substituted with R⁴;

[0024] even more preferably phenyl ortho substituted with R^(4a), and

[0025] heteroaryl selected from isoquinolyl, quinolyl, pyridyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, and benzthiazolyl, wherein heteroaryl isortho-substituted with R^(4a);

[0026] wherein R² is independently selected from H, halo, R³, R⁸, —NHR³,—NHR⁵, —NHR⁶, —NR⁵R⁵, —NR⁵R⁶, —SR⁵, —SR⁶, —SR³, —OR⁵,—OR⁶, —OR³,—C(O)R³, heterocyclyl optionally substituted with 1-4 independent R⁴ oneach ring, and

[0027] C₁-C₁₀ alkyl optionally substituted with 1-4 independent R⁴;

[0028] preferably halo, R³, R⁸, —NHR³, —NHR⁵, —NHR⁶, —NR⁵R⁵, —NR⁵R⁶,—SR⁵, —SR⁶, —SR³, —OR⁵, —OR⁶, —OR³, —C(O)R³, 4-10 membered heterocyclyloptionally substituted with 1-4 independent R⁴, and C₁-C₄ alkyloptionally substituted with 1-3 independent R⁴;

[0029] more preferably halo, —NHR³, —NHR⁵, —NHR⁶, —NR⁵R⁵, 6-10 memberedheterocyclyl optionally substituted with 1-2 independent R⁴, and C₁-C₂alkyl optionally substituted with 1-3 substituents independentlyselected from phenyl, R⁸, chloro, fluoro, OR⁵, OC(O)R⁵, NR⁵R⁵ and COOR⁵;

[0030] even more preferably fluoro, chloro, bromo, —NHR⁵, and methyloptionally substituted with a radical selected from phenyl, R⁹, chloro,fluoro, OR⁵, OC(O)R⁵, NR⁵R⁵ and COOR⁵;

[0031] wherein R³ is independently selected from phenyl optionallysubstituted with 1-5 independent R⁴, and heteroaryl optionallysubstituted with 1-4 independent R⁴;

[0032] preferably phenyl optionally substituted with 1-3 independent R⁴,and heteroaryl optionally substituted with 1-2 independent R⁴; and

[0033] more preferably phenyl optionally substituted with R⁴, and 5-10membered heteroaryl optionally substituted with R⁴;

[0034] wherein R⁴ is independently selected from H, C₁-C₁₀ alkyl,

[0035] C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, aryl, R⁸, halo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁵R¹⁶,COOR⁵, NO₂, CN, C(O)R⁵, C(O)C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)R⁵,S(O)_(n)NR⁵R⁵, NR⁵C(O)NR⁵R⁵, NR⁵C(O)C(O)R⁵, NR⁵C(O)R⁵, NR⁵(COOR⁵),NR⁵C(O)R⁸, NR⁵S(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)R⁵, NR⁵S(O)_(n)R⁸,NR⁵C(O)C(O)NR⁵R⁵, NR⁵C(O)C(O)NR⁵R⁶, OC(O)NR⁵R⁵, OS(O)_(n)NR⁵R⁵,NR⁵S(O)_(n)OR⁵, P(O)(OR⁵)₂, C₁-C₁₀ alkyl substituted with 1-3substituents independently selected from aryl, R⁷ and R⁸, and C₂-C₁₀alkenyl substituted with 1-3 substituents substituents independentlyselected from aryl, R⁷ and R⁸;

[0036] preferably H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, phenyl, R⁸, halo selected from fluoroand chloro, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁵R¹⁶, COOR⁵, NO₂, CN,C(O)C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)NR⁵R⁵,NR⁵C(O)C(O)R⁵, NR C(O)R⁵, NR (COOR⁵), NR⁵C(O)R⁸, NR⁵S(O)_(n)NR⁵R⁵,NR⁵S(O)_(n)R⁵, NR⁵S(O)_(n)R⁸, NR⁵C(O)C(O)NR⁵R⁵, NR⁵C(O)C(O)NR⁵R⁶,OC(O)NR⁵R⁵, OS(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)OR⁵, C₁-C₆ alkyl substituted with1-3 substituents independently selected from phenyl, R⁷ and R⁸; and

[0037] C₂-C₆ alkenyl substituted with 1-3 substituents independentlyselected from phenyl, R⁷ or R⁸;

[0038] more preferably H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,C₃-C₆ cycloalkyl, phenyl, R⁸, chloro, fluoro, OR⁵, OC(O)R⁵, NR⁵R⁵,NR⁵R⁶, NR⁵R¹⁶, COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)R⁵,S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁵, NR⁵(COOR⁵), NR⁵C(O)R⁸, NR⁵S(O)_(n)R⁵,NR⁵S(O)_(n)R⁸, NR⁵S(O)_(n)OR⁵, C₁-C₄ alkyl substituted with 1-3substituents independently selected from phenyl, R⁷ and R⁸; and

[0039] C₂-C₄ alkenyl substituted with 1-3 substituents independentlyselected from phenyl, R⁷ and R⁸;

[0040] even more preferably C₁-C₄ alkyl, optionally substituted phenyl,chloro, fluoro, OR⁵, and C₁-C₄ alkyl substituted with 1-3 substituentsindependently selected from optionally substituted phenyl and R⁸;

[0041] wherein R^(4a) is —NR⁵R¹⁶ or —CH₂NR⁵R¹⁶;

[0042] preferably —NR⁵R¹⁶; and more preferably —NHR¹⁶;

[0043] wherein R⁵ is independently selected from

[0044] H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₄-C₁₀ cycloalkenyl, aryl, C₁-C₁₀ alkyl substituted with 1-3substituents independently selected from aryl, R⁷ or R⁹ groups;

[0045] C₃-C₁₀ cycloalkyl substituted with 1-3 substituents independentlyselected from aryl, R⁷ or R⁹ groups; and

[0046] C₂-C₁₀ alkenyl substituted with 1-3 substituents independentlyselected from aryl, R⁷ or R⁹;

[0047] preferably H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, phenyl, R⁹, C₁-C₆ alkyl substituted with1-3 substituents independently selected from phenyl, R⁷ or R⁹ groups,C₃-C₆ cycloalkyl substituted with 1-3 substituents independentlyselected from phenyl, R⁷ and R⁹ groups, and C₂-C₆ alkenyl substitutedwith 1-3 substituents independently selected from phenyl, R⁷ and R⁹;

[0048] more preferably H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, phenyl, R⁹,C₁-C₄ alkyl substituted with 1-3 substituents independently selectedfrom aryl, R⁷ or R⁹ groups, and C₃-C₁₀ cycloalkyl substituted with 1-3substituents independently selected from aryl, R⁷ or R⁹ groups; and

[0049] even more preferably H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, optionallysubstituted phenyl, R⁹, and C₁-C₃ alkyl substituted with 1-3substituents independently selected from optionally substituted phenyl,R⁷ or R⁹ groups;

[0050] wherein R^(5a) is aryl and R⁹;

[0051] preferably optionally substituted phenyl and R^(9a);

[0052] wherein R⁶ is independently selected from C(O)R⁵, COOR⁵,

[0053] C(O)NR⁵R⁵, C(═NR⁵)NR⁵R⁵, and S(O)_(n)R⁵;

[0054] preferably C(O)R⁵;

[0055] wherein R⁷ is independently selected from halo, CF₃, SR10, OR¹⁰,OC(O)R¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰,OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, N(R¹⁰) (COOR¹⁰),S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)R¹⁰, and P(O)(OR⁵)₂;

[0056] preferably chloro, fluoro, CF₃, SR¹⁰, OR¹⁰, OC(O)R¹⁰,NR¹⁰R¹⁰,NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰,N(R¹⁰)C(O)R¹⁰, N(R¹⁰))(COOR¹⁰), S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)NR¹⁰R¹⁰ andNR¹⁰S(O)_(n)R¹⁰;

[0057] more preferably chloro, fluoro, CF₃, SR¹⁰, OR¹⁰, OC(O)R¹⁰R,NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, C(O)NR¹⁰R¹⁰,N(R¹⁰)C(O)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, and NR¹⁰S(O)_(n)R¹⁰;

[0058] even more preferably chloro, fluoro, CF₃, OR¹⁰, NR¹⁰R¹⁰, COOR¹⁰,NO₂, CN, and C(O)R¹⁰;

[0059] wherein R⁸ is independently selected from 3-8 memberedmonocyclic, 7-12 membered bicyclic, and 11-14 membered tricyclic ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatomsindependently selected from O, N, or S, which may be saturated orunsaturated, and wherein 0, 1, 2, 3 or 4 atoms of each ring may besubstituted by a substituent independently selected from C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl,aryl, R⁹, halo, sulfo, oxo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁶R⁶,COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)NR⁵R⁵,NR⁵C(O)R⁹, NR⁵S(O)_(n)NR⁵R⁵ NR⁵S(O)_(n)R⁹, C₁-C₁₀ alkyl substituted with1-3 substituents independently selected from R⁷, R⁹ and aryl; and C₂-C₁₀alkenyl substituted with 1-3 substituents independently selected fromR⁷, R⁹ and aryl;

[0060] preferably 3-8 membered monocyclic, and 7-12 membered bicyclicring system comprising 1-3 heteroatoms if monocyclic, or 1-6 heteroatomsif bicyclic, said heteroatoms independently selected from O, N, or S,which may be saturated or unsaturated, and wherein 0, 1, 2, 3 or 4 atomsof each ring may be substituted by substituents independently selectedfrom C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆cycloalkenyl, phenyl, R⁹, chloro, fluoro, oxo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵,NR⁵R⁶, NR⁶R⁶, COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵,NR⁵C(O)NR⁵R⁵, NR⁵C(O)R⁹, NR⁵S(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)R⁹, C₁-C₆ alkylsubstituted with 1-3 substituents independently selected from R⁷, R⁹ andphenyl, and C₂-C₆ alkenyl substituted with 1-3 substituentsindependently selected from R⁷, R⁹ and phenyl;

[0061] more preferably 3-8 membered monocyclic, and 7-12 memberedbicyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, said heteroatoms independently selected from O,N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2, 3or 4 atoms of each ring may be substituted by a substituentindependently selected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl, R⁹, phenyl,chloro, fluoro, oxo, OR OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁶R⁶, COOR⁵, NO₂, CN,C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁹, NR⁵S(O)_(n)R⁹, and C₁-C₄alkyl substituted with 1-3 substituents independently selected from R⁷,R⁹ and phenyl;

[0062] even more preferably 5-6 membered heteroaryl optionallysubstituted with C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl, optionallysubstituted phenyl, R⁹, OR⁵, NR⁵R⁵, COOR⁵ , C(O)R⁵, OC(O)R⁵, andC(O)NR⁵R⁵;

[0063] wherein R^(8a) is independently selected from 3-8 memberedmonocyclic, 7-12 membered bicyclic, and 11-14 membered tricyclic ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatomsindependently selected from O, N, or S, which may be saturated orunsaturated, and wherein 0, 1, 2, 3 or 4 atoms of each ring may besubstituted by a substituent independently selected from C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl,aryl, R⁹, halo, sulfo, oxo, SR, OR, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁶R⁶, COOR⁵,NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)NR⁵R⁵, NR⁵C(O)R⁹,NR⁵S(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)R⁹, C₁-C₁₀ alkyl substituted with 1-3substituents independently selected from R⁷, R⁹ and aryl; and C₂-C₁₀alkenyl substituted with 1-3 substituents independently selected fromR⁷, R⁹ and aryl;

[0064] preferably selected from 5-6 membered monocyclic, or 9-10membered bicyclic ring system, comprising 1-3 heteroatoms if monocyclic,or 1-6 heteroatoms if bicyclic, said heteroatoms independently selectedfrom O, N, or S, which may be saturated or unsaturated, and wherein 0,1, 2, 3 or 4 atoms of each ring may be substituted by substituentsindependently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, phenyl, R⁹, halo, oxo, SR⁵, OR⁵,OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁶R⁶, COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵,S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁹, NR⁵S(O)_(n)R⁹, C₁-C₆ alkyl substituted with1-3 substituents independently selected from R⁷, R⁹ and phenyl, andC₂-C₆ alkenyl substituted with 1-3 substituents independently selectedfrom R⁷, R⁹ and phenyl;

[0065] provided R^(8a) is substituted with C(O)NHR a;

[0066] preferably 5-6 membered monocyclic, or 9-10 membered

[0067] bicyclic ring system, comprising 1-3 heteroatoms if monocyclic,or 1-6 heteroatoms if bicyclic, said heteroatoms independently selectedfrom O, N, or S, which may be partially saturated or unsaturated, andwherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by asubstituent independently selected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl,R⁹, oxo, phenyl, chloro, fluoro, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, COOR⁵, NO₂,CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁹, NR⁵S(O)_(n)R⁹, andC₁-C₄ alkyl substituted with 1-3 substituents independently selectedfrom R⁷, R⁹ and phenyl;

[0068] provided R^(8a) is substituted with C(O)NHR^(5a);

[0069] more preferably 5-6 membered monocyclic heteroaryl, or 9-10membered bicyclic heteroaryl comprising 1-2 heteroatoms if monocyclic,or 1-4 heteroatoms if bicyclic, said heteroatoms independently selectedfrom O, N, or S, and wherein 0, 1, or 2 atoms of each ring may besubstituted by substituents independently selected from C₁-C₄ alkyl,optionally substituted phenyl, R⁹, chloro, fluoro, oxo, OR⁵, and C₁-C₄alkyl substituted with 1-3 substituents independently selected from R⁷,R⁹ and optionally substituted phenyl;

[0070] provided R^(8a) is substituted with C(O)NHR^(5a);

[0071] wherein R⁹ is independently a 3-8 membered monocyclic, 7-12membered bicyclic, or 11-14 membered tricyclic ring system comprising1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms independently selected fromO, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2or 3 atoms of each ring may be substituted by a substituentindependently selected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C10alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl, halo, sulfo, oxo,haloalkyl, SR¹⁰, OR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN,C(O)R¹⁰, S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰;

[0072] preferably 3-8 membered monocyclic, a 7-12 membered bicyclic,ring system comprising 1-3 heteroatoms if monocyclic, or 1-6 heteroatomsif bicyclic, said heteroatoms independently selected from O, N, or S,which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms ofeach ring may be substituted by a substituent independently selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, oxo, C₁-6 haloalkyl, OR¹⁰,NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, S(O)_(n)R¹⁰,S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰;

[0073] more preferably 3-8 membered monocyclic, or 7-12 memberedbicyclic, ring system comprising 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms independently selected from O,N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent independentlyselected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl, fluoro, chloro, oxo, C₁-C₄haloalkyl, OR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰,S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰;

[0074] even more preferably 5-6 membered heteroaryl, or 9-10 memberedbicyclic heteroaryl comprising 1-2 heteroatoms if monocyclic, 1-4heteroatoms if bicyclic, said heteroatoms independently selected from O,N, or S, and wherein 0, 1, or 2 atoms of each ring may be substituted bya substituent independently selected from C₁-C₄ alkyl, halo, C₁-C₄haloalkyl, optionally substituted phenyl, R⁸, OR¹⁰, NR¹⁰R¹⁰, COOR¹⁰,C(O)R¹⁰, OC(O)R¹⁰, and C(O)NR¹⁰R¹⁰;

[0075] wherein R^(9a) is independently a 5-6 membered monocyclic, or

[0076] 9-10 membered bicyclic ring system comprising 1-3 heteroatoms ifmonocyclic, or 1-6 heteroatoms if bicyclic, said heteroatomsindependently selected from 0, N, or S, which may be saturated orunsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may besubstituted by a substituent independently selected from C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl,halo, oxo, C₁₋₆ haloalkyl, SR¹⁰, OR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹,COOR¹⁰, NO₂, CN, C(O)R₁₀, S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰;

[0077] preferably 3-8 membered monocyclic, or 7-12 membered bicyclicring system comprising 1-3 heteroatoms if monocyclic, or 1-6 heteroatomsif bicyclic, said heteroatoms independently selected from O, N, or S,which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms ofeach ring may be substituted by a substituent independently selectedfrom C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆cycloalkenyl, oxo, chloro, fluoro, C₁-C₄ haloalkyl, SR¹⁰, OR¹⁰, NR¹⁰R¹⁰,NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, S(O)_(n)R¹⁰,S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰;

[0078] more preferably 5-6 membered monocyclic, or 9-10 memberedbicyclic ring system comprising 1-2 heteroatoms if monocyclic, or 1-3heteroatoms if bicyclic, said heteroatoms independently selected from O,N, or S, which may be saturated or unsaturated, and wherein 0, 1, or 2atoms of each ring may be substituted by a substituent independentlyselected from C₁-C₃ alkyl, halo, oxo, C₁-C₃ haloalkyl and OR¹⁰;

[0079] wherein R¹⁰ is independently H; C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl, haloalkyl,C₁-C₁₀ alkyl optionally substituted with 1-3 substituents independentlyselected from C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, halo, CF₃, OR¹², SR¹², NR¹²R¹², COOR¹², NO₂, CN, C(O)R¹²,C(O)NR¹²R¹², NR¹²C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹², and OC(O)R¹²;and phenyl optionally substituted with 1-3 substituents independentlyselected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₄-C₁₀ cycloalkenyl, halo, CF₃, OR¹², SR¹², NR¹²R¹², COOR¹²,NO₂, CN, C(O)R¹², C(O)NR¹²R¹², NR¹²C(O)R¹², N(R¹²)(COOR¹²),S(O)_(n)NR¹²R¹², and OC(O)R¹²;

[0080] preferably H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, C₁-C₆ alkyl substituted with 1-3independent, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, halo, OR¹², SR¹², NR¹²R¹², COOR¹², NO₂, CN, C(O)R¹²,C(O)NR¹²R¹², NR¹²C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹² and OC(O)R¹²,and phenyl optionally substituted with 1-3 substituents independentlyselected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, halo, OR¹², SR¹², NR¹²R¹², COOR¹², NO₂,CN, C(O)R¹², C(O)NR¹²R¹², NR¹²C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹²,and OC(O)R¹²;

[0081] more preferably H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, CJ-C₄ alkyloptionally substituted with 1-3 substituents independently selected fromC₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, OR¹², SR¹², NR¹²R²,COOR¹² ₁ chloro, fluoro, NO₂, CN, C(O)R , C(O)NR¹²R¹², NR¹²C(O)R¹²,S(O)_(n)NR¹²R , and OC(O)R¹²; and

[0082] phenyl optionally substituted with 1-3 substituents independentlyselected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, OR¹², SR¹², NR¹²R¹², COOR¹², NO₂, CN,C(O)R¹², C(O)NR¹²R¹², chloro, fluoro, NR¹²C(O)R¹², N(R¹²)(COOR¹²),S(O)_(n)NR¹²R¹² and OC(O)R¹²;

[0083] even more preferably H, methyl and C₁-C₃ alkyl substituted with1-3 substituents independently selected from fluoro, chloro, hydroxy,methoxy, optionally substituted phenyl and R⁹, and optionallysubstituted phenyl;

[0084] wherein R¹¹ is independently selected from C(O)R¹⁰, COOR¹⁰,C(O)NR¹⁰R¹⁰ and S(O)_(n)R¹⁰;

[0085] wherein R¹² is independently selected from H, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl,C₁-C₁₀ alkyl substituted with 1-3 substituents independently selectedfrom C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, halo, OR¹³, SR¹³, NR¹³R¹³, COOR¹³, NO₂, CN, C(O)R¹³,C(O)NR¹³R¹³, NR¹³C(O)R¹³, and OC(O)R¹³, and phenyl optionallysubstituted with 1-3 substituents independently selected from C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, halo, OR¹³, SR¹³, NR¹³R¹³, COOR¹³, NO₂, CN, C(O)R¹³,C(O)NR¹³R¹³, NR¹³C(O)R¹³, and OC(O)R¹³;

[0086] preferably H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkylsubstituted with 1-3 substituents independently selected from C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl, halo,OR¹³, NR¹³R¹³, COOR¹³, NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R³, andOC(O)R¹³, and phenyl optionally substituted with 1-3 substituentsindependently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halo, OR¹³, NR¹³R³, COOR¹³, NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³,and OC(O)R¹³;

[0087] more preferably H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkylsubstituted with 1-3 substituents independently selected from C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, OR¹³, SR¹³, fluoro, chloro,NR¹³R¹³, COOR¹³, NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³, andOC(O)R¹³, and phenyl optionally substituted with 1-3 substituentsindependently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, CF₃, OR¹³, SR¹³, NR¹³R¹³, COOR¹³,fluoro, chloro, NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³, andOC(O)R¹³;

[0088] wherein R¹³ is independently selected from H, C₁-C₁₀ alkyl,

[0089] C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, C₁-C₁₀ alkyl optionally substituted with halo, OR¹⁴, SR¹⁴,NR¹⁴R¹⁴, COOR¹⁴, NO₂, and CN, and phenyl optionally substituted withhalo, CF₃, OR¹⁴, SR¹⁴, NR¹⁴R¹⁴, COOR¹⁴, NO₂, and CN;

[0090] preferably H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkyloptionally substituted with halo, CF₃, OR¹⁴, NR¹⁴R¹⁴, COOR¹⁴, NO₂, andCN, and phenyl optionally substituted with halo, OR¹⁴, NR¹⁴R¹⁴, COOR¹⁴,NO₂, and CN;

[0091] more preferably H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkyloptionally substituted with OR¹⁴ NR¹⁴R¹⁴ and COOR¹⁴ and phenyloptionally substituted with halo, CF₃, OR¹⁴, NR¹⁴R¹⁴, and COOR¹⁴;

[0092] wherein R¹⁴ is independently selected from H, C₁-C₁₀ alkyl,C₃-C₁₀ cycloalkyl and phenyl;

[0093] preferably H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl and phenyl;

[0094] more preferably H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl and phenyl;

[0095] wherein R¹⁶ is independently selected from C₄-C₁₀ cycloalkenyl,aryl, and R⁸; provided aryl is substituted with C(O)NHR^(5a);

[0096] preferably phenyl and R^(8a); provided phenyl is substituted withC(O)NHR^(5a);

[0097] wherein n is independently 1 or 2;

[0098] preferably 2; and

[0099] wherein aryl is independently a 6-carbon monocyclic, 10-carbonbicyclic or 14-carbon tricyclic aromatic ring system optionallysubstituted with 1-3 substituents independently selected from C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, R⁹, halo, haloalkyl, CF₃, OR¹⁰, SR¹⁰, NR¹⁰R¹⁰, NR¹⁰R ,COOR¹⁰ NO₂, CN, C(O)R¹⁰, C(O)C(O)R¹⁰, C(O)NR⁵R⁵, N(R¹⁰)C(O)NR¹⁰R¹⁰,N(R¹⁰)C(O)R¹⁰R, N(R¹⁰)S(O)_(n)R¹⁰, N(R¹⁰)(COOR¹⁰), NR¹⁰C(O)C(O)R¹⁰,NR¹⁰C(O)R¹⁰, NR¹⁰S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)R⁹, NR¹²C(O)C(O)NR¹²R¹²,S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, OC(O)R¹⁰, C₁-C₁₀ alkyl substituted with1-3 substituents independently selected from R⁹, halo, CF₃, OR¹⁰, SR¹⁰,OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹⁰, COOR¹⁰, NO₂, CN, C(O)R¹⁰,OC(O)NR¹⁰R¹⁰, C(O)NR⁵R⁵, N(R¹⁰)C(O)R¹⁰, N(R¹⁰)(COOR¹⁰), S(O)_(n)NR¹⁰R¹⁰;R¹⁰; and

[0100] C₂-C₁₀ alkenyl substituted with 1-3 substituents independentlyselected from R⁹, halo, CF₃, OR¹⁰, SR10, OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰,NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰N(R¹⁰)C(O)R¹⁰, N(R¹⁰)(COOR¹⁰O) and S(O)_(n)NR¹⁰R¹⁹;

[0101] preferably phenyl is optionally substituted with 1-3 substituentsindependently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, R⁹, halo, CF₃, OR¹⁰, SR¹⁰ ,NR¹⁰R¹⁰, NR¹⁰R¹¹ ₁ COOR¹⁰, NO₂, CN, C(O)R¹⁰, C(O)C(O)R¹⁰, C(O)NR⁵R⁵,N(R¹⁰)C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, N(R¹⁰)S(O)_(n)R¹⁰, N (R¹⁰)(COOR¹⁰),NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)R⁹, NR10 S(O)_(n)NR¹ ¹⁰R¹⁰, NR¹⁰S(O)_(n)R⁹,NR¹²C(O)C(O)NR¹²R², S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, OC(O)R¹⁰, C₁-C₆ alkylsubstituted with 1-3 substituents independently selected from R⁹, halo,OR , SR¹⁰, OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R COOR , NO₂, CN, C(O)R¹ ,OC(O)NR¹⁰R¹, C(O)NR⁵R⁵, N(R¹⁰)C(O)R¹⁰, N (R¹⁰)(COOR¹⁰), andS(O)_(n)NR¹⁰R¹⁰; and

[0102] C₂-C₆ alkenyl substituted with 1-3 substituents independentlyselected from R⁹, halo, CF₃, OR¹⁰, SR¹⁰ OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰,NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰,N(R¹⁰)C(O)R¹⁰, N(R¹⁰)(COOR¹⁰) and S(O)_(n)NR¹⁰R¹⁰;

[0103] more preferably optionally substituted phenyl is optionallysubstituted with 1-3 substituents independently selected from C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, R⁹, C₁-C₄,haloalkyl, fluoro, chloro, OR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN,C(O)R¹⁰, C(O)NR⁵R⁵, N(R¹⁰)C(O)R¹⁰, N(R¹⁰)S(O)_(n)R¹⁰, NR¹⁰C(O)R⁹,NR¹⁰S(O)_(n)R⁹, S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, OC(O)R¹⁰, C₁-C₄ alkylsubstituted with 1-3 substituents independently selected from R⁹,fluoro, chloro, OR¹, SR¹⁰, OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰ ,NO₂, CN, C(O)R¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR⁵R⁵, N (R¹⁰)C(O)R¹⁰ , andS(O)_(n),NR¹⁰R¹⁰; and

[0104] C₂-C₄ alkenyl substituted with 1-3 substituents independentlyselected from R⁹, halo, OR¹⁰, SR¹⁰c, OC(O)R¹R, NR¹¹R¹¹, NR¹⁰R¹⁰ ₁NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, OC(O)NR¹⁰R¹⁰,C(O)NR¹⁰R¹⁰N(R¹⁰)C(O)R¹⁰, and S(O)_(n)NR¹⁰R¹⁰;

[0105] even more preferably phenyl is optionally substituted with 1-3substituents independently selected from C₁-C₃ alkyl, R⁹, fluoro,chloro, C₁-C₃ haloalkyl, OR¹⁰, NR¹⁰R¹⁰, COOR¹⁰, C(O)R¹⁰, C(O)NR⁵R⁵,OC(O)R¹⁰, and C₁-C₃ alkyl substituted with 1-2 substituentsindependently selected from phenyl and R⁹;

[0106] and pharmaceutically acceptable salts thereof.

[0107] The invention also relates to compounds wherein R¹ is

[0108] wherein R^(1a) is selected from unsubstituted or substitutedaryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,preferably phenyl, tetrahydronaphthyl, naphthyl, isocuinolyl, quinolyl,pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl,benzimidazolyl, benzoxazolyl, and benzthiazolyl;

[0109] wherein R^(1a) is substituted with one or more substituentsindependently selected from halo, C₁₋₆-alkyl, optionally substitutedC₃₋₆-cycloalkyl, optionally substituted phenyl, C₁₋₆-haloalkoxy,optionally substituted phenyloxy, benzyl, optionally substituted 5-6membered heterocyclyl-C₁C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁₋₆-haloalkyl, and C₁₋₆-alkoxy;

[0110] preferably wherein R^(1a) is substituted with one or moresubstituents independently selected from chloro, fluoro, amino, hydroxy,cyclohexyl, phenylmethyl, morpholinylmethyl, ethyl,methylpiperdinylmethyl, methyl, propyl, isopropyl, butyl, tert-butyl,sec-butyl, isobutyl, methylpiperazinylmethyl, trifluoromethyl,phenyloxy, methoxy and ethoxy; and

[0111] wherein R² is selected from fluoro, chloro, bromo, NHR⁵ andmethyl optionally substituted with 1-3 substituents independentlyselected from phenyl, R⁹, chloro, fluoro, OR⁵, OC(O)R⁵, —NR⁵R⁵ andCOOR⁵;

[0112] preferably —NHR⁵, fluoro, chloro, bromo, benzyl, trifluoromethyl,hydroxymethyl, methoxymethyl, aminomethyl and methyl;

[0113] wherein R⁴ is selected from C₁-C₄ alkyl, optionally substitutedphenyl, chloro, fluoro, hydroxy, methoxy and benzyl;

[0114] wherein R⁵ is independently selected from H, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl; C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, phenyloptionally substituted with R⁴, R⁹, and C₁-C₄ alkyl substituted with 1-3substituents independently selected from aryl, R⁷ and R⁹ groups;

[0115] preferably H, methyl and phenyl optionally substituted withchloro, fluoro, hydroxy, and methoxy; and

[0116] wherein R⁹ is selected from 5-6-membered heteroaryl, and

[0117] wherein 0, 1, 2 or 3 atoms of each ring may be substituted by asubstituent independently selected from C₁-C₄ alkyl, fluoro, chloro,trifluoromethyl, optionally substituted phenyl, hydroxy, methoxy, amino,methylamino, carboxy, methoxycarbonyl, formyl, methylcarbonyl, acetyl,and aminocarbonyl;

[0118] and pharmaceutically acceptable salts thereof.

[0119] The invention also relates to compounds of Formula II

[0120] wherein A¹, A² and A³ are independently selected from C, CH, O,S, N and NH;

[0121] wherein ring Z is selected from

[0122] a) 5- or 6-membered heteroaryl, preferably

[0123] I) 5-membered heteroaryl selected from thienyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl,triazolyl and isothiazolyl, even more preferably 5-membered heteroarylselected from more specifically

[0124] II) preferably 6-membered heteroaryl selected from pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, even more preferably6-membered heteroaryl selected from

[0125] more specifically

[0126] b) phenyl, even more preferably

[0127] wherein X^(a) is selected from

[0128] preferably X^(a) is selected from

[0129] more preferably X¹ is

[0130] wherein Z^(a) is oxygen or sulfur;

[0131] wherein R^(1a) is selected from

[0132] a) substituted or unsubstituted 6-10 membered aryl, preferablyphenyl, naphthyl, indenyl, or tetrahydronaphthyl, more preferablyphenyl,

[0133] b) substituted or unsubstituted 5-6 membered heterocyclyl,preferably 5-6 membered heteroaryl, more preferably thienyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,thiadiazolyl, furyl, or pyrrolyl,

[0134] c) substituted or unsubstituted 9-10 membered fused heterocyclyl,preferably 9-10 membered fused heteroaryl, more preferably indazolyl,indolyl, benzothiadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl,benzodioxanyl, or quinazolinyl;

[0135] d) cycloalkyl, and

[0136] e) cycloalkenyl;

[0137] wherein R^(1a) is optionally substituted with one or moresubstituents independently selected from halo, —OR¹⁵, —SR¹⁵, —CO₂R¹⁵,—CONR¹⁵R¹⁵, —COR¹⁵, —NR¹⁵R¹⁵ —NH(C₁-C₄ alkylenylR¹⁵), —SO₂R¹⁵,—SO₂NR¹⁵R¹⁵, —NR¹⁵C(O)OR¹⁵, —NR¹⁵C(O)R¹⁵, optionally substitutedcycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionallysubstituted phenyl, lower alkyl substituted with R⁴, cyano, nitro, loweralkenyl and lower alkynyl;

[0138] preferably substituted with one or more substituentsindependently selected from halo, —OR¹⁵, —SR¹⁵, —SO₂R¹⁵, —CO₂R¹⁵,—CONR¹⁵R¹⁵, —COR¹⁵, —NR¹⁵R¹⁵, —NH (C₁-C₂ alkylenylR¹⁵), —(C₁-C₂alkylenyl)NR¹⁵R¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵C(O)OR¹⁵, —NR¹⁵C(O)R¹⁵, optionallysubstituted cycloalkyl, optionally substituted 5-6 memberedheterocyclyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₂-alkylenyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₂-alkylenyl, C₁₋₄-alkyl, cyano, C₁₋₄-hydroxyalkyl, nitroand C₁₋₂-haloalkyl;

[0139] more preferably R^(1a) is unsubstituted or substituted with oneor more substituents selected from chloro, fluoro, bromo, methoxy,phenyloxy, benzyl, methylthio, methyl, ethyl, propyl, butyl, isopropyl,isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, hydroxymethyl, cyano, carboxy, aminocarbonyl,methylcarbonyl, amino, methylamino, cyclopropyl, cyclohexyl,piperidinyl, morpholinyl, N-methylpiperazinyl, N-ethylpiperazinyl,morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl,methyl aminothiocarbonyl, N-methylamino-methylenyl, optionallysubstituted phenyl, N, N-diethylamino, and N, N-dimethylamino;

[0140] wherein R^(z) is C₁-C₄ alkylenyl, where one of the CH₂ groups maybe substituted with O or —NH—;

[0141] preferably C₁-C₂ alkylenyl, where one of the CH₂ groups may besubstituted with O or —NH—;

[0142] more preferably —CH₂CH₂- or —CH₂-;

[0143] wherein R⁴ and R^(4b) are independently selected from H, C₁-C₃alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆cycloalkenyl, phenyl, 5-6 membered heterocyclyl, halo, CF₃, SR⁵, OR⁵,OC(O)R⁵, NR⁵R⁵, COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)R⁵,S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁵, NR⁵(COOR⁵), NR⁵S(O)_(n)R⁵, OC(O)NR⁵R⁵,OS(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)OR⁵, C₁-C₆ alkyl substituted with 1-3substituents independently selected from optionally substituted phenyland optionally substituted 5-6 membered heterocyclyl, and

[0144] C₂-C₆ alkenyl substituted with 1-3 substituents independentlyselected from optionally substituted phenyl and optionally substituted5-6 membered heterocyclyl;

[0145] preferably R⁴ is selected from H, C₁-C₃ alkyl, C₂-C₃ alkenyl,C₃-C₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, fluoro, chloro, CF₃,SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵, COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, SO₂R⁵,SO₂NR⁵R⁵, NR⁵SO₂R⁵, and C₁-C₆ alkyl substituted with 1-3 substituentsindependently selected from optionally substituted phenyl and optionallysubstituted 5-6 membered heteroaryl;

[0146] more preferably H, methyl, phenyl, fluoro, chloro, CF₃, methoxy,methoxymethyl, acetyl, amino, methoxycarbonyl and benzyl;

[0147] wherein R^(4b) is H;

[0148] wherein R⁵ is selected from HI lower alkyl, phenyl and loweraralkyl;

[0149] preferably H, methyl and ethyl;

[0150] wherein R⁵b is independently selected from H, C₁-C₄ alkyl, phenyloptionally substituted with R⁴, and C₁-C₄ alkyl substituted with 1-3substituents independently selected from R⁴, preferably H, C₁-C₂ alkyl,phenyl optionally substituted with R⁴, and methyl substituted with 1-3substituents independently selected from phenyl, fluoro, chloro, CF₃,methoxy, acetyl, amino, methoxycarbonyl, and more preferably H, ormethyl;

[0151] wherein R¹⁵ is independently selected from H, lower alkyl,phenyl, 5-6 membered heterocyclyl, C₃-C₆ cycloalkyl, and lowerhaloalkyl;

[0152] preferably H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl, andC₁₋₂-haloalkyl;

[0153] wherein R³⁰ is selected from H, methyl, phenyl, and benzyl; and

[0154] wherein n is 0, 1 or 2;

[0155] and pharmaceutically acceptable salts thereof;

[0156] A family of specific compounds of particular interest withinFormula I consists of compounds and pharmaceutically-acceptable saltsthereof as follows:3-[3-(4-Amino-[1,3,5]triazin-2-yl)-pyridin-2-ylamino]-N-(3-isopropyl-phenyl)-benzamide;N-(4-phenoxyphenyl)-3-{l-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzimidazo-1-2-ylamino}benzamide;N-(4-chlorophenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzamide;N-(phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide;N-(4-phenoxy-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzamide;and3-[3-(4-amino-[1,3,5]triazin-2-yl)-pyridin-2-ylamino]-N-(4-phenoxy-phenyl)benzamide.

[0157] Indications

[0158] Compounds of the present invention are useful for, but notlimited to, the prevention or treatment of angiogenesis relateddiseases. The compounds of the invention have kinase inhibitoryactivity, such as VEGFR/KDR inhibitory activity. The compounds of theinvention are useful in therapy as antineoplasia agents.

[0159] Compounds of the invention are useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

[0160] The compounds of the present invention are also useful in thetreatment of cancer related indications such as solid tumors, sarcomas(especially Ewing's sarcoma and osteosarcoma), retinoblastoma,rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, includingleukemia and lymphoma, tumor-induced pleural or pericardial effusions,and malignant ascites.

[0161] Preferably, the compounds are useful for the treatment ofneoplasia selected from lung cancer, colon cancer and breast cancer.

[0162] The compounds also would be useful for treatment ofophthalmological conditions such as corneal graft rejection, ocularneovascularization, retinal neovascularization includingneovascularization following injury or infection, diabetic retinopathy,retrolental fibroplasia and neovascular glaucoma; retinal ischemia;vitreous hemorrhage; ulcerative diseases such as gastric ulcer;pathological, but non-malignant, conditions such as hemangiomas,including infantile hemaginomas, angiofibroma of the nasopharynx andavascular necrosis of bone; and disorders of the female reproductivesystem such as endometriosis. The compounds are also useful for thetreatment of edema, and conditions of vascular hyperpermeability.

[0163] The compounds of the invention are useful in therapy ofproliferative diseases. These compounds can be used for the treatment ofan inflammatory rheumatoid or rheumatic disease, especially ofmanifestations at the locomotor apparatus, such as various inflammatoryrheumatoid diseases, especially chronic polyarthritis includingrheumatoid arthritis, juvenile arthritis or psoriasis arthropathy;paraneoplastic syndrome or tumor-induced inflammatory diseases, turbideffusions, collagenosis, such as systemic Lupus erythematosus,poly-myositis, dermato-myositis, systemic sclerodermia or mixedcollagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof. An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further especiallyapplicable to the treatment of inflammation, e.g. inflammatory diseaseor condition, of connective tissues including dermatomyositis andmyositis.

[0164] These compounds can be used as active agents against such diseasestates as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limb, woundhealing, peptic ulcer Helicobacter related diseases, fractures, catscratch fever, rubeosis, neovascular glaucoma and retinopathies such asthose associated with diabetic retinopathy or macular degeneration. Inaddition, some of these compounds can be used as active agents againstsolid tumors, malignant ascites, hematopoictic cancers andhyperproliferative disorders such as thyroid hyperplasia (especiallyGrave's disease), and cysts (such as hypervascularity of ovarian stroma,characteristic of polycystic ovarian syndrome (Stein-Leventhalsyndrome)) since such diseases require a proliferation of blood vesselcells for growth and/or metastasis.

[0165] Further, some of these compounds can be used as active agentsagainst burns, chronic lung disease, stroke, polyps, anaphylaxis,chronic and allergic inflammation, ovarian hyperstimulation syndrome,brain tumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema,pachydermoperiostosis and male infertility, ascites, and other diseaseswhere vascular hyperpermeability, effusions, exudates, proteinextravasation, or edema is a manifestation of the disease. The compoundswill also be useful in treating disorders in which protein extravasationleads to the deposition of fibrin and extracellular matrix, promotingstromal proliferation (e.g. fibrosis, cirrhosis and carpal tunnelsyndrome).

[0166] VEGF's are unique in that they are the only angiogenic growthfactors known to contribute to vascular hyperpermeability and theformation of edema. Indeed, vascular hyperpermeability and edema that isassociated with the expression or administration of many other growthfactors appears to be mediated via VEGF production. Thus the compoundsare also useful for the treatment of vascular hyperpermeability.

[0167] Inflammatory cytokines stimulate VEGF production. Hypoxia resultsin a marked upregulation of VEGF in numerous tissues, hence situationsinvolving infarct, occlusion, ischemia, anemia, or circulatoryimpairment typically invoke VEGF/VPF-mediated responses. Vascularhyperpermeability, associated edema, altered transendothelial exchangeand macromolecular extravasation, which is often accompanied bydiapedesis, can result in excessive matrix deposition, aberrant stromalproliferation, fibrosis, and the like. Hence, VEGF-mediatedhyperpermeability can significantly contribute to disorders with theseetiologic features. Thus the compounds of the present invention areuseful in the treatment of VEGF-mediated hyperpermeability.

[0168] The compounds of the present invention are also useful in thetreatment of ulcers including bacterial, fungal, Mooren ulcers andulcerative colitis.

[0169] The compounds of the present invention are also useful in thetreatment of conditions wherein undesired angiogenesis, edema, orstromal deposition occurs in viral infections such as Herpes simplex,Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections andtoxoplasmosis, following trauma, radiation, stroke, endometriosis,ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis,synovitis, Crohn's disease, sickle cell anemia, Lyme disease,pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendudisease, chronic inflammation, chronic occlusive pulmonary disease,asthma, an inflammatory rheumatoid or rheumatic disease.

[0170] The compounds of the present invention are also useful in thetreatment of ocular conditions such as ocular and macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-lasercomplications, conjunctivitis, Stargardt's disease and Eales disease inaddition to retinopathy and macular degeneration.

[0171] The compounds of the present invention are also useful in thetreatment of cardiovascular conditions such as atherosclerosis,restenosis, arteriosclerosis, vascular occlusion and carotid obstructivedisease.

[0172] The compounds of the present invention are also useful in thetreatment of diabetic conditions such as glaucoma, diabetic retinopathyand microangiopathy.

[0173] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0174] As used herein, the compounds of the present invention includethe pharmaceutically acceptable derivatives thereof.

[0175] Definitions

[0176] The term “treatment” includes therapeutic treatment as well asprophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a preclinically evident stage ofdisorders in individuals). The term “prevention” includes eitherpreventing the onset of disorders altogether or delaying the onset of apreclinically evident stage of disorders in individuals. This includesprophylactic treatment of those at risk of developing a disease, such asa cancer, for example. “Prophylaxis” is another term for prevention.

[0177] A “pharmaceutically-acceptable derivative” denotes any salt,ester of a compound of this invention, or any other compound which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by being therapeutically-effective in vivo.

[0178] The phrase “therapeutically-effective” is intended to qualify theamount of each agent, which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies. For example, effective neoplastictherapeutic agents prolong the survivability of the patient, inhibit therapidly-proliferating cell growth associated with the neoplasm, oreffect a regression of the neoplasm.

[0179] The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

[0180] Where the term “alkyll” is used, either alone or within otherterms such as “haloalkyl” and “alkylamino”, it embraces linear orbranched radicals having one to about twelve carbon atoms. Morepreferred alkyl radicals are “lower alkyl” radicals having one to aboutsix carbon atoms. Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isoamyl, hexyl and the like. Even more preferred are lower alkylradicals having one or two carbon atoms. The term “alkylenyl” embracesbridging divalent alkyl radicals such as methylenyl and ethylenyl. Theterm “lower alkyl substituted with R²” does not include an acetalmoiety.

[0181] The term “alkenyl” embraces linear or branched radicals, havingat least one carbon-carbon double bond, of two to about twelve carbonatoms. More preferred alkenyl radicals are “lower alkenyl” radicalshaving two to about six carbon atoms. Most preferred lower alkenylradicals are radicals having two to about four carbon atoms. Examples ofalkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

[0182] The term “alkynyl” denotes linear or branched radicals, having atleast one carbon-carbon triple bond, having two to about twelve carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about six carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like.

[0183] The term “halo” means halogens such as fluorine, chlorine,bromine or iodine atoms.

[0184] The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, said atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, aswell as any substitutents thereon, may be attached at any atom thatallows a stable compound to be formed. The term “nonaromatic” ring orring system refers to the fact that at least one, but not necessarilyall, rings in a bicyclic or tricyclic ring system is nonaromatic.

[0185] Leaving groups are species that may be detached from a .moleculeduring a reaction and are known in the art. Examples of such groupsinclude, but are not limited to, halogen groups (e.g., I, Br, F, Cl),sulfonate groups (e.g., mesylate, tosylate), sulfide groups (e.g.,SCH₃), and the like. Nucleophiles are species that may be attached to amolecule during reaction and are known in the art. Examples of suchgroups include, but are not limited to, amines, Grignard reagents,anionic species (e.g., alkoxides, amides, carbanions) and the like.

[0186] The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms. Even more preferred are lowerhaloalkyl radicals having one to three carbon atoms. Examples ofhaloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

[0187] The term “hydroxyalkyl” embraces linear or branched alkylradicals having one to about ten carbon atoms any one of which may besubstituted with one or more hydroxyl radicals. More preferredhydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one tosix carbon atoms and one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl. Even more preferred are lowerhydroxyalkyl radicals having one to three carbon atoms.

[0188] The term “alkoxy” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are “lower alkoxy” radicals having one tosix carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

[0189] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one or two rings

[0190] wherein such rings may be attached together in a fused manner.The term “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl.Said “aryl” group may have 1 to 3 substituents such as lower alkyl,hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.

[0191] The term “heterocyclyl” embraces saturated, partially saturatedand unsaturated heteroatom-containing ring-shaped radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. It doesnot include rings containing —O—O—,—O—S— or —S—S— portions. Said“heterocyclyl” group may have 1 to 3 substituents such as hydroxyl,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

[0192] Examples of saturated heterocyclic radicals include saturated 3to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

[0193] Examples of unsaturated heterocyclic radicals, also termed“heteroaryl” radicals, include unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

[0194] The term also embraces radicals where heterocyclic radicals arefused/condensed with aryl radicals: unsaturated condensed heterocyclicgroup containing 1 to 5 nitrogen atoms, for example, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl]. Preferred heterocyclic radicals include five to tenmembered fused or unfused radicals. More preferred examples ofheteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl,thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferredheteroaryl radicals are 5- or 6-membered heteroaryl, containing one ortwo heteroatoms selected from sulfur, nitrogen and oxygen, selected fromthienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyland pyrazinyl.

[0195] The term “sulfonyl”, whether used alone or linked to other termssuch as alkylsulfonyl, denotes respectively divalent radicals —SO₂—.

[0196] The terms “carboxy” or “carboxyl”, whether used alone or withother terms, such as “carboxyalkyl”, denotes —CO₂H.

[0197] The term “aralkyl” embraces aryl-substituted alkyl radicals.Preferable aralkyl radicals are “lower aralkyl” radicals having arylradicals attached to alkyl radicals having one to six carbon atoms. Evenmore preferred are “phenylalkylenyl” attached to alkyl portions havingone to three carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

[0198] The term “heterocyclylalkylenyl” embracesheterocyclyl-substituted alkyl radicals. Preferable heterocyclylalkylenyl radicals are “lower heterocyclylalkylenyl” radicals havingheterocyclyl radicals attached to alkyl radicals having one to sixcarbon atoms. More preferred are heterocyclyl-C₁-C₂-alkylenyl radicalssuch as morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, and the like.

[0199] The term “carbonyl”, whether used alone or with other terms, suchas “aminocarbonyl”, denotes —(C═O)—.

[0200] The term “alkylamino” embraces “N-alkylamino” and“N,N-dialkylamino” where amino groups are substituted with one alkylradical and with two alkyl radicals, respectively. More preferredalkylamino radicals are “lower alkylamino” radicals having one or twoalkyl radicals of one to six carbon atoms, attached to a nitrogen atom.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Suitable alkylamino radicals may be mono or dialkylaminosuch as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylaminoor the like.

[0201] The term “cycloalkyl” includes saturated carbocyclic groups.Preferred cycloalkyl groups include C₃-C₆ rings. More preferredcompounds include, cyclopentyl, cyclopropyl, and cyclohexyl.

[0202] The term “cycloalkenyl” includes carbocyclic groups have one ormore carbon-carbon double bonds. “Cycloalkenyl” and “cycloalkyldienyl”compounds are included. Preferred cycloalkenyl groups include C₃-C₆rings. More preferred compounds include, for example, cyclopentenyl,cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

[0203] The term “comprising” is meant to be open ended, including theindicated component but not excluding other elements.

[0204] The present invention preferably includes compounds thatselectively inhibit KDR.

[0205] The present invention also comprises the use of a compound of theinvention, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment either acutely orchronically of an angiogenesis mediated disease state, including thosedescribed previously. The compounds of the present invention are usefulin the manufacture of an anti-cancer medicament. The compounds of thepresent invention are also useful in the manufacture of a medicament toattenuate or prevent disorders through inhibition of KDR.

[0206] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulasI-II in association with a least one pharmaceutically-acceptablecarrier, adjuvant or diluent.

[0207] The present invention also comprises a method of treatingangiogenesis related disorders, in a subject, the method comprisingtreating the subject having or susceptible to such disorder with atherapeutically-effective amount of a compound of the present invention.

[0208] Combinations

[0209] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered at the same time orsequentially at different times, or the therapeutic agents can be givenas a single composition.

[0210] The phrase “co-therapy” (or “combination-therapy”), in defininguse of a compound of the present invention and another pharmaceuticalagent, is intended to embrace administration of each agent in asequential manner in a regimen that will provide beneficial effects ofthe drug combination, and is intended as well to embraceco-administration of these agents in a substantially simultaneousmanner, such as in a single capsule having a fixed ratio of these activeagents or in multiple, separate capsules for each agent.

[0211] Specifically, the administration of compounds of the presentinvention may be in conjunction with additional therapies known to thoseskilled in the art in the prevention or treatment of neoplasia, such aswith radiation therapy or with cytostatic or cytotoxic agents.

[0212] If formulated as a fixed dose, such combination products employthe compounds of this invention within the accepted dosage ranges.Compounds of Formula I may also be administered sequentially with knownanticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with, or after administration of the knownanticancer or cytotoxic agent.

[0213] Currently, standard treatment of primary tumors consists ofsurgical excision followed by either radiation or IV administeredchemotherapy. The typical chemotherapy regime consists of either DNAalkylating agents, DNA intercalating agents, CDK inhibitors, ormicrotubule poisons. The chemotherapy doses used are just below themaximal tolerated dose and therefore dose limiting toxicities typicallyinclude, nausea, vomiting, diarrhea, hair loss, neutropenia and thelike.

[0214] There are large numbers of antineoplastic agents available incommercial use, in clinical evaluation and in pre-clinical development,which would be selected for treatment of neoplasia by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.

[0215] A first family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku OF-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

[0216] A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

[0217] A third family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantibiotic-type antineoplastic agents. Suitable antibiotic-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone,Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II,Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A,bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067,Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-MyersBMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-l,Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin,Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa HakkoDC₈₉-A1, Kyowa Hakko DC₉₂-B, ditrisarubicin B, Shionogi DOB-41,doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954,Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin,kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa HakkoKT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American CyanamidLL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone,SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon KayakuNKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

[0218] A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B. cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones,_ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

[0219] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as acemannan,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide,anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002(Novelos), bexarotene, bicalutamide, broxuridine, capecitabine,celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate,DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin,dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol,doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine,fluorouracil, HIT diclofenac, interferon alfa, daunorubicin,doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur,epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,gimeracil/oteracil/tegafur combination, glycopine, goserelin,heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-N1, interferon alfa-n3, interferonalfacon-1, interferon alpha, natural, interferon beta, interferonbeta-1a, interferon beta-1b, interferon gamma, natural interferongamma-1a, interferon gamma-1b, interleukin-1beta, iobenguane,irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide,lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon,leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone,mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine,nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesisstimulating protein, NSC 631570 octreotide, oprelvekin, osaterone,oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferonalfa-2b, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, rabbit antithymocyte polyclonal antibody, polyethyleneglycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed,rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab,romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran,sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin,tazarotene, tegafur, temoporfin, temozolomide, teniposide,tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan,tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factoralpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine,melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941(Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide,diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,etanidazole, fenretinide, filgrastim SDO (Amgen), fulvestrant,galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), SU6668 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine,thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine(Biomira), melanoma vaccine (New York University), melanoma vaccine(Sloan Kettering Institute), melanoma oncolysate vaccine (New YorkMedical College), viral melanoma cell lysates vaccine (Royal NewcastleHospital), or valspodar.

[0220] The invention relates to inhibitors of enzymes that catalyzephosphoryl transfer and/or that bind ATP/GTP nucleotides, compositionscomprising the inhibitors, and methods of using the inhibitors andinhibitor compositions. The inhibitors and compositions comprising themare useful for treating or modulating disease in which phosphoryltransferases, including kinases, may be involved, symptoms of suchdisease, or the effect of other physiological events mediated byphosphoryl transferases, including kinases. The invention also providesfor methods of making the inhibitor compounds and methods for treatingdiseases in which one or more phosphoryl transferase, including kinase,activities is involved.

[0221] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as other kinaseinhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors,metallomatrix proteases inhibitors (MMP), COX-2 inhibitors includingcelecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's,SOD mimics or α_(v)β₃ inhibitors.

[0222] The present invention comprises a process for the preparation ofa compound of Formula I-II.

[0223] Compounds of the present invention can possess, in general, oneor more asymmetric carbon atoms and are thus capable of existing in theform of optical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

[0224] Compounds of the present invention can possess, in general,tautomeric forms, which are included in the family of compounds inFormula I-II.

[0225] Also included in the family of compounds of Formula I-II are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-II may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areacetic, adipic, algenic, anthranilic, ascorbic, aspartic, benzoic,benzenesulfonic, butyric, camphoric, camphorsulfonic, citric,cyclopentanepropionic, cyclohexylaminosulfonic, digluconic,dodecylsulfonic, ethanesulfonic, formic, fumaric, galactaric,galacturonic, glycolic, gluconic, glucuronic, glucoheptanoic, glutamic,glycerophosphonic, heptanoic, hexanoic, 4-hydroxybenzoic,2-hydroxyethanesulfonic, β-hydroxybutyric, lactic, malic, maleic,mandelic, mesylic, methanesulfonic, nicotinic, 2-naphthalenesulfonic,oxalic, palmoic, pectinic, pivalic, persulfuric, 2-phenylpropionic,picric, pyruvic, propionic, phenylacetic, embonic (pamoic), cyclopentaneproprionic, pantothenic, toluenesulfonic, salicylic, sulfanilic,stearic, succinic, tartaric, thiocyanic, and undecanoic.

[0226] Suitable pharmaceutically-acceptable base addition salts ofcompounds of Formula I-II include metallic salts, such as salts madefrom alkali metals and alkaline earth metals including, for example,aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, orsalts made from organic bases including primary, secondary and tertiaryamines, substituted amines including cyclic amines, such as caffeine,arginine, diethylamine, N-ethyl piperidine, histidine, glucamine,isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine,piperidine, ammonia, triethylamine, trimethylamine. All of these saltsmay be prepared by conventional means from the corresponding compound ofthe invention by reacting, for example, the appropriate acid or basewith the compound of Formula I-II.

[0227] Also, the basic nitrogen-containing groups can be quaternizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chloride, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

[0228] Additional examples of such salts can be found in Berge et al.,J. Pharm. Sci., 66, 1 (1977).

[0229] Combinations of substituents and variables envisioned by thisinvention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow preparation.

[0230] As used herein, the compounds of this invention, including thecompounds described herein, are defined to include pharmaceuticallyacceptable derivatives or prodrugs thereof. A “pharmaceuticallyacceptable derivative or prodrug” means any pharmaceutically acceptablesalt, ester, salt of an ester, or other derivative of a compound of thisinvention which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this invention.Particularly favored derivatives and prodrugs are those that increasethe bioavailability of the compounds of this invention when suchcompounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies. Preferred prodrugs include derivatives where a group whichenhances aqueous solubility or active transport through the gut membraneis appended to the structure of formulas described herein.

[0231] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts. This invention also envisions the quaternization of anybasic nitrogen-containing groups of the compounds disclosed herein.Water or oil-soluble or dispersible products may be obtained by suchquaternization.

[0232] The invention relates to a process for making a compound of anyof the formulas described herein, comprising reacting a triazine of oneor more of the formulas:

[0233] with an appropriate nucleophilic agent or agents, wherein thegroups in said formulas are as defined herein.

[0234] In one embodiment, the invention relates to a process for makinga compound of any of the formulas described herein, comprising reactinga triazine of one or more of the formulas:

[0235] with an appropriate nucleophilic agent or agents, wherein L isdefined as a leaving group and the groups in said formulas are asdefined herein.

[0236] General Synthetic Procedures

[0237] The compounds of the invention can be synthesized according tothe following procedures of Schemes 1-18,

[0238] wherein the substituents are as defined for Formulas I-II, above,except where further noted.

[0239] 2,4-Dichloro-triazine 1 can be prepared according to the methodset out in Scheme 1. Similar to that described by E. Allenstein, Z.Anorg. Allgem. Chem, 322, 265 (1963), sodium dicyanamide in water isreacted with concentrated HCl at a temperature of about −18-35° C. togive N-cyanochloroformamidine. N-Cyanochloroformamidine is added to asolution of DMF and POC₁ ₃ in a solvent, such as CH₂Cl₂, preferably at atemperature at about RT, to give 2,4-dichloro-1,3,5-triazine 1, similarto the method described by R. Harris, Synthesis, 11, 907, (1981).

[0240] Monoamine substituted triazines 2 and di-substituted triazines 3can be prepared according to the method set out in Scheme 2.2,4-Dichloro-1,3,5-triazine 1 is coupled with amines, in the presence ofbase, such as DIEA, and a solvent, such as DMF, at a temperature ofabout 0° C. to about RT to give 4-chloro-[1,3,5]triazin-2-yl)amine 2.

[0241] Alternatively, 2,4-dichloro-1,3,5-triazine 1 is coupled with anamine in the presence of K₂CO₃, such as suspended in an organic solvent,such as AcCN, to yield triazines 2. Preferably the reaction is held at atemperature below RT, and more preferably at about 0° C.

[0242] Monoamine substituted triazines 2 are reacted with a heterocyclicgroup having an active hydrogen, such as an NH group, such as insolvent, such as IpOH, and in the presence of base, such as DIEA, togive the di-substituted triazine 3. Preferably the reaction is heated,more preferably at a temperature of about >75° C., even more preferablyat a temperature of about 100° C. Alternatively, ethers, thioethers andthe like can be prepared by substituting other nucleophiles for theamines described above.

[0243] Ureas (X is O) or thioureas (X is S) 5 can be prepared accordingto the method set out in Scheme 3. Amines 4 are reacted with isocyanatesor thioisocyantes to give the corresponding urea derivatives 5.

[0244] Amide substituted triazines 6 (where R⁵ is not H) can be preparedaccording to the method set out in Scheme 4. Amines 4 are reacted withacylating reagents, such as acid halides, to give the correspondingamide derivatives 6.

[0245] Cyclic amides can be prepared according to the method set out inScheme 5. The amino group of compound 7 (where R⁰ is alkyl, aryl, andthe like) is protected, such as with Boc anhydride, followed bytreatment to remove the ester, such as with base, forming the protectedamine/free acid 8. Alternatively, other amino protecting groups known inthe art can be used. Substituted amines are coupled with the free acid,such as with EDC, to form the protected amine/amide 9. The protectedamine moiety is removed, such as with acid, and reacted withtriazinyl-pyridinyl compounds to form the[([1,3,5]triazin-2-yl)-pyridin-2-ylamino]amide compounds 10. Preferablythe amination is performed neat, and at a temperature between aboveabout 50° C., and more preferably at about 90° C. to about 120° C.

[0246] Alternatively, compounds 12 can be prepared from mixedacid/amines 11 as shown in Scheme 6. Substituted amines are coupled withthe mixed acid/amines 11 such as with a coupling reagent, for exampleEDC, to form the mixed amine/amide 12.

[0247] Substituted carboxamides 10 can be prepared from thecorresponding halo analogs 13 by the process outlined in Scheme 7.Substituted amino acids 14 are prepared from the corresponding chlorocompounds 13 such as by reacting with an amine at a suitabletemperature, such as about 80° C. The acid 14 is coupled with an amine,preferably in the presence of a coupling agent such as EDC, to form thecorresponding amide 10.

[0248] The amination process can be carried out as an Ullmann typereaction using a copper catalyst, such as copper[0] or a copper[I]compound such as copper[I]oxide, copper[I]bromide or copper[I]iodide inthe presence of a suitable base (such as a metal carbonate, for exampleK₂CO₃) to neutralize the acid generated in the reaction. This reactionis reviewed in Houben-Weyl “Methoden der Organischen Chemie”, Band 11/1,page 32-33, 1958, in Organic Reactions, Volume 14, page 19-24, 1965 andby J. Lindley (1984) in Tetrahedron, Volume 40, page 1433-1456. Theamount of catalyst is typically in the range of 1 to 20 mole percent.The reaction is carried out in an inert, aprotic solvent such as anether (for example dimethoxyethane or dioxane) or an amide (for exampleDMF or N-methylpyrrolidone), under an inert atmosphere in thetemperature range of 60-180° C.

[0249] An alternative amination process involves using a Group VIIIelement, where the metal core of the catalyst should be a zero-valenttransition metal, such as palladium or nickel, which has the ability toundergo oxidative addition to the Aryl-Halogen bond. The zero valentstate of the metal may be generated in situ from the M[II] state. Thecatalyst complexes may include chelating ligands, such as alkyl, aryl orheteroaryl derivatives of phoshines or biphosphines, imines or arsines.Preferred catalysts contain palladium or nickel. Examples of suchcatalysts include palladium[II]chloride, palladium[II]acetate,tetrakis(triphenyl-phosphine)palladium[0] and nickel[II]acetylacetonate.The metal catalyst is typically in the range of 0.1 to 10 mole percent.The chelating ligands may be either monodentate, as in the case forexample of trialkyphosphines, such as tributylphosphine,triarylphosphines, such as tri-(ortho-tolyl)phosphine, and triheteroarylphosphines, such as tri-2-furylphosphine; or they may be bidentate suchas in the case of 2,2′-bis(diphenylphosphino)-1,1′binaphthyl,1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferroceneand 1-(N,N-dimethyl-amino)-1′-(dicyclohexylphosphino)biphenyl. Thesupporting ligand may be complexed to the metal center prior to beingadded in the form of a metal complex to the reaction mixture or may beadded to the reaction mixture as a separate compound. The supportingligand is typically present in the range 0.01 to 20 mole percent. It isoften necessary to add a suitable base to the reaction mixture, such asa trialkylamine (for example DIEA or1,5-diazabicyclo[5,4,O]undec-5-ene), a Group I alkali metal alkoxide(for example potassium tert-butoxide) or carbonate (for example cesiumcarbonate) or potassium phosphate. The reaction is typically carried outin an inert aprotic solvent such as an ether (for exampledimethoxyethane or dioxane) or an amide (for example DMF orN-methylpyrrolidone), under an inert atmosphere in the temperature rangeof about 60 to about 180° C.

[0250] The amination is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example DMF or dimethylacetamide, a cyclicether, for example THF or dioxane, or a nitrile, for example AcCN, or ina mixture thereof, at an appropriate temperature, for example in atemperature range of from about 40° C. to about 180° C., and ifnecessary under an inert gas atmosphere, for example a nitrogen or argonatmosphere.

[0251] Substituted carboxamides 10 can be prepared from thecorresponding halo analogs 13 by the process outlined in Scheme 8. Thechloro acid 13 is coupled with an amine, preferably in the presence of acoupling agent such as EDC, to form the corresponding chloro amide 15.Substituted amino-amides 10 are prepared from the corresponding chlorocompounds 15 such as by reacting with an amine at a suitabletemperature, such as about 80° C. The amination reaction can be run inthe presence of an appropriate catalyst such as a palladium catalyst, inthe presence of an aprotic base such as sodium t-butoxide or cesiumcarbonate, or a nickel catalyst, or a copper catalyst.

[0252] Substituted carboxamides 10 can be prepared from thecorresponding bromo/chioro analogs 16 by the process outlined in Scheme9. Trhe bromo/chloro acid 16 is coupled with an amine, preferably in thepresence of a coupling agent such as EDC, to form the correspondingbromo 10 substituted amide 17. Suzuki coupling with the bromo amide 17and suitable boronic acids provides the substituted amide 15.Substituted amino-amides 10 are prepared from the corresponding chlorocompounds 15 as described in Scheme 6.

[0253] Substituted pyridyltriazines 18, 19 and 20 can be prepared fromthe corresponding cyanopyridine analogs 16 by the process outlined inScheme 10. For example, 2-chloronicotinonitrile 16 is reacted with HClin the presence of a dry alcohol, preferably at a temperature below RT.Ammonium acetate is added to form the amidine which is reacted withcyanamide in the presence of aqueous base, such as of 5% aqueous NaHCO₃to form the cyanoamidine 17. Similar to the methodology of Scheme 3,cyanoamidine 17 is converted to the 2-chloro-[1,3,5]triazine 18 byreacting with POC₁ ₃ and in a solvent such as DMF, preferably at aboutRT. 2-Chloro-4-(2-chloropyrid-3-yl)-[l,3,5]triazine 18 reacts with anoptionally substituted amine (where R⁵ is as defined in the formulasherein) to produce 2-amino-4-(2-chloropyrid-3-yl)-triazines 19. Theremaining chloride may then be displaced by reaction with amine (neat orin a small amount of solvent) at an elevated temperature to form the2-amino-4-(2-aminopyrid-3-yl)-triazines 20.

[0254] Substituted pyridyltriazines 23, 24 and 25 can be prepared fromthe corresponding pyridyl thioamides 21 by the process outlined inScheme 11. For example, the thioamide of 2-chloroisonicotinamide[prepared according to Libermann, et al. Memoires Presentes a la SocieteChimigue 1958, 694-702] is alkylated, such as with methyl iodide. Theresulting thioimidate salt is reacted with ammonium acetate in analcohol, such as in IpOH to provide the amidine. This material isreacted with H₂NCN in the presence of base, such as NaHCO₃, and asolvent containing an alcohol such as IpOH, and H₂O, to obtain thecyanoamidine 22. This material is converted to the2-chloro-[l,3,5]triazine 23 by reacting with POC₁ ₃ and DMF at atemperature at RT or below RT. The 2-chloro-[1,3,5]triazine 23 reactswith an optionally substituted amine (where R⁵ is as defined in theformulas herein) to produce 2-heterocyclic triazines 24. The remainingchloride may then be displaced by reaction with amine (neat or in asmall amount of solvent) at an elevated temperature to form the2-heterocyclic triazines 25.

[0255] With use of the general procedure outlined in Schemes 1-11,3-nitroamidines provide entry to a variety of aryl substitutions.Reduction of the nitroarene to the amine may be followed, for example,by acylation, reductive amination, sulfonylation, or urea formation toprovide compounds exemplified above with independent R³, R⁵, and R¹¹ asdefined in the formulas herein.

[0256] With use of the general procedure outlined in Schemes 1-11,6-chloro-pyridine-2-carbonitrile [Elman, B. Tetrahedron, 1985, 41,4941-4948] may be functionalized to provide the pyridinyl [1,3,5]triazinylamines exemplified above with independent R³,R⁵ and R¹⁰asdefined in the formulas herein.

[0257] With use of the general procedure outlined in Schemes 1-11,2-chloro-4-aryl-3-pyridine-carbonitriles [Church, R.; Trust, R.;Albright, J. D.; Powell, D. W. J. Org. Chem. 1995, 60, 3750-3758] may befunctionalized to provide the pyridinyl[1,3,5]-triazinylaminesexemplified above with independent R³, R⁵ and R¹⁶ as defined in theformulas herein.

[0258] Substituted triazines can be prepared according to the method setout in Scheme 15, similar to that described by M. J. Sharp, et al.Tetrahedron Letters, 1987, 28, 5093-5096. Monoamine substitutedtriazines 2 are reacted with substituted boronic acids such as in thepresence of tetrakis (triphenylphosphine) palladium(O), in anappropriate organic solvent, such as EtOH, to yield the disubstitutedtriazine 35. Preferably the reaction is heated to above RT, morepreferably to a temperature where the solvent is at reflux.

[0259] Substituted triazines 38 can be prepared according to the methodset out in Scheme 16. Substituted indoles 37 in an appropriate solvent,such as DMF, is reacted with NaH (producing a strong gas evolution).This mixture is reacted with a chlorotriazine 36, such as at an elevatedtemperature, preferably about 100° C., forming the desired triazine 38.

[0260] Substituted triazines can be prepared according to the method setout in Scheme 17, similar to that described by Chakrabarti and Tupper,J. of Het. Chem., 1974, 11, 417-421. Cyanuric chloride is dissolved in asolvent, such as toluene. Pyrrole is added, the tube is sealed, and thereaction heated at a temperature above RT, preferably above about 50°C., more preferably at about 80° C. This gives the dichlorideintermediate compound 41. Displacement of the chloride with anappropriate amine under standard conditions, followed by reduction ofthe remaining chloride by hydrogenation under standard conditionsresults in the desired product 42.

[0261] Cyclic amides can be prepared according to the method set out inScheme 18. The nitro acid halide 43 is aminated, followed by reductionof the nitro group to form the amine/amide 44. Substituted amine/amide44 are coupled with the triazinyl-pyridinyl compounds to form the[([1,3,5]triazin-2-yl)-pyridin-2-ylamino]amide compounds 10.

[0262] The starting compounds defined in Schemes 1-18 may also bepresent with functional groups in protected form if necessary and/or inthe form of salts, provided a salt-forming group is present and thereaction in salt form is possible. If so desired, one compound offormula I can be converted into another compound of formula I or aN-oxide thereof; a compound of formula I can be converted into a salt; asalt of a compound of formula I can be converted into the free compoundor another salt; and/or a mixture of isomeric compounds of formula I canbe separated into the individual isomers.

[0263] N-Oxides can be obtained in a known matter by reacting a compoundof formula I with hydrogen peroxide or a peracid, e.g.3-chloroperoxy-benzoic acid, in an inert solvent, e.g. CH₂Cl₂, at atemperature between about −10 to about 35° C., such as about 0° C. toabout RT.

[0264] If one or more other functional groups, for example carboxy,hydroxy, amino, or mercapto, are or need to be protected in a compoundof Formulas I-II, because they should not take part in the reaction,these are such groups as are usually used in the synthesis of peptidecompounds, and also of cephalosporins and penicillins, as well asnucleic acid derivatives and sugars.

[0265] The protecting groups may already be present in precursors andshould protect the functional groups concerned against unwantedsecondary reactions, such as acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned above and hereinafter.

[0266] The protection of such functional groups by such protectinggroups, the protecting groups themselves, and their removal reactionsare described for example in standard reference works, such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973, in T. W. Greene, “Protective Groups in OrganicSynthesis”, Wiley, New York 1981, in “The Peptides”; Volume 3 (editors:E. Gross and J. Meienhofer), Academic Press, London and New York 1981,in “Methoden der organischen Chemie” (Methods of organic chemistry),Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart1974, in H. -D. Jakubke and H. Jescheit, “Aminosäuren, Peptide,Proteine” (Amino acids, peptides, proteins), Verlag Chemie, Weinheim,Deerfield Beach, and Basel 1982, and in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide und Derivate” (Chemistry of carbohydrates:monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

[0267] In the additional process steps, carried out as desired,functional groups of the starting compounds which should not take partin the reaction may be present in unprotected form or may be protectedfor example by one or more of the protecting groups mentioned aboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

[0268] Salts of a compound of formula I with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds offormula I may thus be obtained by treatment with an acid or with asuitable anion exchange reagent. A salt with two acid molecules (forexample a dihalogenide of a compound of formula I) may also be convertedinto a salt with one acid molecule per compound (for example amonohalogenide); this may be done by heating to a melt, or for exampleby heating as a solid under a high vacuum at elevated temperature, forexample from about 130 to about 170° C., one molecule of the acid beingexpelled per molecule of a compound of formula I.

[0269] Salts can usually be converted to free compounds, e.g. bytreating with suitable basic agents, for example with alkali metalcarbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically K₂CO₃ or NaOH.

[0270] A compound of formula I, wherein X^(a) is oxygen, can beconverted into the respective compound wherein X^(a) is sulfur, forexample, by using an appropriate sulfur compound, e. g. using reactionwith Lawesson's reagent(2,4-bis-(4-methoxyphenyl)2,4-dithioxo-1,2,3,4-dithiaphosphetan) in ahalogenated carbon hydrate, such as CH₂Cl₂, or an aprotic solvent, suchas toluene or xylene, at temperatures from about 30° C. to reflux.

[0271] All process steps described here can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralizing agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from about −100° C. to about 190° C.,preferably from about −80° C. to about 150° C., for example at about −80to about 60° C., at RT, at about −20 to about 40° C. or at the boilingpoint of the solvent used, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example, under argon or nitrogen.

[0272] Salts may be present in all starting compounds and transients, ifthese contain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

[0273] In certain cases, typically in hydrogenation processes, it ispossible to achieve stereoselective reactions, allowing for exampleeasier recovery of individual isomers.

[0274] The solvents from which those can be selected which are suitablefor the reaction in question include, for example, water, esters,typically lower alkyl-lower alkanoates, e.g EtOAc, ethers, typicallyaliphatic ethers, e.g. Et₂O, or cyclic ethers, e.g. THF, liquid aromatichydrocarbons, typically benzene or toluene, alcohols, typically MeOH,EtOH, IpOH or 1-propanol, nitrites, typically AcCN, halogenatedhydrocarbons, typically CH₂Cl₂, acid amides, typically DMF, bases,typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids,typically lower alkanecarboxylic acids, e.g. HOAc, carboxylic acidanhydrides, typically lower alkane acid anhydrides, e.g. aceticanhydride, cyclic, linear, or branched hydrocarbons, typicallycyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g.aqueous solutions, unless otherwise stated in the description of theprocess.

[0275] The invention relates also to those forms of the process in whichone starts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the referredembodiment, one starts from those starting materials which lead to thecompounds described above as preferred.

[0276] The compounds of formula I-II, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

[0277] New starting materials and/or intermediates, as well as processesfor the preparation thereof, are likewise the subject of this invention.In the preferred embodiment, such starting materials are used andreaction conditions so selected as to enable the preferred compounds tobe obtained.

[0278] Starting materials of the invention, are known, are commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art.

[0279] In the preparation of starting materials, existing functionalgroups which do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the examples.

[0280] All remaining starting materials are known, capable of beingprepared according to known processes, or commercially obtainable; inparticular, they can be prepared using processes as described in theexamples.

[0281] The following examples contain detailed descriptions of themethods of preparation of compounds of Formulas I-II. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention.

[0282] The compounds of this invention may contain one or moreasymmetric centers and thus occur as racemates and racemic mixtures,scalemic mixtures, single enantiomers, individual diastereomers anddiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included in the present invention. The compounds of thisinvention may also be represented in multiple tautomeric forms, forexample, as illustrated below:

[0283] The invention expressly includes all tautomeric forms of thecompounds described herein. The compounds may also occur in cis- ortrans- or E- or Z- double bond isomeric forms. All such isomeric formsof such compounds are expressly included in the present invention. Allcrystal forms of the compounds described herein are expressly includedin the present invention.

[0284] Substituents on ring moieties (e.g., phenyl, thienyl, etc.) maybe attached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

[0285] The compounds of this invention may contain heterocyclic ringsystems attached to another ring system. Such heterocyclic ring systemsmay be attached through a carbon atom or a heteroatom in the ringsystem.

[0286] Alternatively, a compound of any of the formulas delineatedherein may be synthesized according to any of the processes delineatedherein. In the processes delineated herein, the steps may be performedin an alternate order and may be preceded, or followed, by additionalprotection/deprotection steps as necesssary. The processes may furthercomprise use of appropriate reaction conditions, including inertsolvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine,K₂CO₃, and the like), catalysts, and salt forms of the above. Theintermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase,simulated moving bed (“SMB”), extraction, distillation, trituration,reverse phase HPLC and the like. Reactions conditions such astemperature, duration, pressure, and atmosphere (inert gas, ambient) areknown in the art and may be adjusted as appropriate for the reaction.

[0287] As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theinhibitor compounds described herein are known in the art and include,for example, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995).

[0288] The compounds of this invention may be modified by appendingappropriate functionalities to enhance selective biological properties.Such modifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

[0289] Unless otherwise noted, all materials were obtained fromcommercial suppliers and used without further purification. Allreactions involving air- or moisture-sensitive compounds were performedunder a nitrogen atmosphere. All parts are by weight and temperaturesare in Degrees centigrade unless otherwise indicated. All compoundsshowed NMR spectra consistent with their assigned structures.

[0290] In order that the invention described herein may be more readilyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

[0291] Analytical Methods

[0292] Unless otherwise indicated all HPLC analyses are run on a HP-1050system with an HP Zorbax SB-C₁₈ (5E) reverse phase column (4.6×150 mm)run at 30° C. with a flow rate of 1.00 ml/min. The mobile phase usedsolvent A (H₂O/0.1% TFA) and solvent B (AcCN/0.1% TFA) with a 20 mingradient from 10% to 90% AcCN. The gradient is followed by a 2 minreturn to 10% AcCN and a 3 min flush. The peaks of interest eluted onthe LC profiles at the times indicated.

[0293] LC-MS Method For

[0294] Method A

[0295] 1. Samples are run on a HP-1100 MSD system with a HP Zorbax SB-C₈(5□) reverse phase column (4.6×50 mm) run at 30° C. with a flow rate of0.75 ml/min.

[0296] 2. The mobile phase used solvent A (H₂O/0% HOAc) and solvent B(AcCN/0.1% HOAc) with a 10 min gradient from 10% to 90% AcCN. Thegradient is followed by a 1 min return to 10% AcCN and a 2 min flush.

[0297] 3. The peaks of interest eluted on the LC profiles at the timesindicated.

[0298] Method B

[0299] 1. Samples are run on an HP-1100 system with an HP Zorbax SB-C₈(5□) reverse phase column (4.6×50 mm) run at 30²C with a flow rate of1.5 ml/min.

[0300] 2. The mobile phase used solvent A (H₂O/0% HOAc) and solvent B(AcCN/0.1% HOAc) with a 5 min gradient from 10% to 90% ACCN. Thegradient is followed by a 0.5 min return to 10% ACCN and a 1.5 minflush.

[0301] 3. The peaks of interest eluted on the LC profiles at the timesindicated.

[0302] Preparative HPLC

[0303] Where indicated, compounds of interest were purified viapreparative HPLC using a Gilson workstation with a 20×50 mm column at 20ml/min. The mobile phase used solvent A (H₂O/0% TFA) and solvent B(AcCN/0.1% TFA) with a 10 min gradient from 5% to 100% AcCN. Thegradient is followed by a 2 min return to 5% AcCN.

[0304] Proton NMR Spectra

[0305] Unless otherwise indicated, all ¹H NMR spectra are run on aVarian series Mercury 300 MHz instrument. All observed protons arereported as parts-per-million (ppm) downfield from tetramethylsilane(TMS) or other internal reference in the appropriate solvent indicated.RT room temperature H₂O water Na₂SO₄ sodium sulfate NaHCO₃ sodiumbicarbonate tBuOMe tert-butylmethoxide DIEA dilsopropylethylamine Et₃Ntriethylamine EDC 1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride DMSO dimethylsulfoxide BSA bovine serum albumin ATPadenosine triphosphate DTT dithiothreitol NaGH sodium hydroxide mgmilligram g gram ml milliliter h hour AcCN acetonitrile THFtetrahydrofuran MeOH methanol EtOH ethanol IpOH isopropanol HOAc aceticacid EtOAc ethyl acetate Et₂O ethyl ether TFA trifluoroacetic acid DMFdimethylformamide POCl₃ phosphoryl chloride CH₂Cl₂ dichloromethane HClhydrochloric acid NH₄Cl ammonium chloride Boc tert-butyloxycarbonyl HOBthydroxybenzotriazole K₂CO₃ potassium carbonate min minutes MeI methyliodide NaH sodium hydride LDA lithium diisopropylamide

[0306] The following abbreviations are used:

[0307] Preparation I

[0308] Sodium dicyanamide (105.9 g, 1.19 mol) was nearly dissolved intoH₂O and added quickly to concentrated HCl (530 ml) pre-cooled to about−18° C. The resulting slurry was stirred at −18° C. for about 15 min,warmed to 35° C. and re-cooled to 10° C. The resulting white precipitatewas filtered, washed with small amounts of H₂0, and dried under vacuumfor 20 h. N-Cyanochloroformamidine (−50 g) was obtained. DMF (27.3 ml)was dissolved in CH₂Cl₂ (550 ml) at RT. POCl₃ (27.3 ml) was added andafter about 5 min, N-cyanochloroformamidine (30 g) was also added. Themixture was stirred overnight at RT, then washed 3 times with H₂O andonce with brine. The organic layer was dried over Na₂SO₄, filtered, andevaporated under reduced pressure. The white solid thus obtained wasidentified as the 2,4-dichloro-1,3,5-triazine.

[0309] Preparation II

[0310] 2,4-Dichloro-1,3,5-triazine (1.054 g, 7.028 mmol) was dissolvedin DMF (5 ml) and cooled to 0° C. To this solution, DIEA (1.225 ml,7.028 mmol) and 3,4,5-trimethoxyaniline (1.185 g, 6.47 mmol) were added.The reaction mixture was kept at 0° C. for 15 to 30 min and at RT for 2h. The reaction mixture was diluted with EtOAc and washed with brine.The organic layer was dried over Na₂SO₄, filtered, and evaporated invacuo. The residue was added to CH₂Cl₂ and the resulting whiteprecipitate was filtered and dried under reduced pressure to give(4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine: MSm/z=279 [M−Cl+OH₂]⁺. Calc'd for C₁₂H₁₃ClN₄O₃: 296.

[0311] Similarly,(3-chloro-4-fluoro-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-amine wasprepared by reacting 2,4-dichlorotriazine with3-chloro-4-fluoro-phenylamine.

[0312] 1-(4-Chloro-[1,3,5]triazin-2-yl)-1H-benzoimidazol-2-ylamine wasprepared according to the above method, substituting the appropriateamines, as a light yellow solid: MS m/z=246 [M+H]⁺. Calc'd for C₁₀H₇ClN₆: 246.04.

[0313] Preparation III

[0314] To a solution of 5-nitroindazole (10 g, 61.3 mmol) in DMF (100mL) was added K₂CO₃ (12.7 g, 91.9 mmol) and PhCH₂Br (7.29 mL, 61.3mmol). The resulting mixture was stirred at RT for 3.5 days, then pouredinto 400 mL of H₂O. The resulting slurry was filtered, rinsed once withwater and dried in vacuo giving a beige solid. A portion of this crudematerial (2.5 g) was purified by chromatography (SiO₂, elution with 1:2EtOAc-hexanes) giving 1-benzyl-5-nitro-1H-indazole and2-benzyl-5-nitro-1H-indazole.

[0315] Preparation IV

[0316] To 1-benzyl-1H-indazol-5-ylamine (906.4 mg (3.58 mmol)) in MeOH(20 mL) and EtOAc (5 mL) at RT was added a slurry of 150 mg of 10% Pd-Cin MeOH (5 mL). The resulting slurry was stirred under a balloon of H₂for 1.2 h, filtered through Celite®, and rinsed with MeOH and EtOAc.Concentration of the filtrate gave 1-benzyl-1H-indazol-5-ylamine as apinkish solid: MS m/z=224 [M+H]⁺. Calc'd for C₁₄H₁₃N₃: 223.11.

[0317] Preparation V

[0318] To 2,4-dichloro-1,2,5-triazine (526.1 mg, 3.51 mmol) in DMF (15mL) at 0° C. was added DIEA (0.733 mL, 4.21 mmol). The resulting yellowsolution was stirred at 0° C. for 20 min and1-benzyl-1H-indazol-5-ylamine (783.5 mg, 3.51 mmol) was added in oneportion followed by 2×2.5 mL DMF flask rinses. The resulting mixture wasstirred at 0° C. for 30 min, at RT for 4.5 h, then diluted with EtOAc.The organic layer was washed twice with water and once with brine. Theaqueous layer and washings were extracted with EtOAc. The combinedorganics were dried, concentrated, and purified by chromatography (Sio₂,elution with 1:1 EtOAc-hexanes) to give a slightly impure pinkish solid.Trituration with Et₂O gave(1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amine as alight pink solid: MS m/z=337 [M+H]⁺. Calc'd for C₁₇H13ClN₆: 336.09.

[0319] Preparation VI

[0320] To (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amine(473 mg, 1.40 mmol) in DMF (7.5 ml) at 0° C. was added MeI (0.262 mL,4.21 mmol), followed by NaH (60% dispersion in oil)(67.4 mg, 1.69 mmol).The resulting mixture was stirred at 0° C. for 4.25 h. An additional 10mg NaH was added after 3.1 h as TLC indicated remaining startingmaterial. At this point, the reaction mixture was quenched with sat'd aqNH₄Cl and diluted with water and EtOAc. The organic layer was washedwith water and brine. The aqueous layer and washings were extracted oncewith EtOAc. The combined organics were dried, concentrated and purifiedby chromatography (SiO₂, elution with 1:1 EtOAc-hexanes) to giveN-methyl-(1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amineas a pale oil: MS m/z=351 [M+H]⁺. Calc'd for C₁₈H₁₅ClN₆: 350.10.

[0321] Preparation VII

[0322] (3-Amino-phenyl)-acetic acid methyl ester was prepared byreacting 3-aminophenylacetic acid with acetyl chloride in MeOH to affordthe corresponding methyl ester, HCl salt, (3.09 g, 15.324 mmol). Theester was dissolved in DMF (5 ml) with DIEA (2.67 ml, 15.324 mmol) andcooled to 0° C. To this solution was added dropwise a 0° C. solution ofDMF (5 ml) containing 2,4-dichloro-1,3,5-triazine (2.297 g, 15.324 mmol)and DIEA (2.67 ml, 15.324 mmol). The reaction was stirred at ODC for 15min and then at RT for 1 h. The reaction mix was diluted with EtOAc andwater. The layers were separated, and the aqueous layer was extractedtwice with EtOAc. The combined organic layers were washed 4 times withbrine and dried over Na₂SO₄. The crude was concentrated down and driedunder reduced pressure, giving[3-(4-chloro-[l,3,5]triazin-2-ylamino)-phenyl]-acetic acid methyl ester(4.3 g, 100%). Similarly, 3-(4-chloro-[l,3,5]triazin-2-ylamino)benzoicacid methyl ester was prepared.

[0323] Preparation VIII

[0324] 2,4-Dichloro-1,3,5-triazine (173.7 mg, 1.158 mmol) was dissolvedin DMF (1 ml). To the stirring solution, cooled to 0° C., was added DIEA(202 μl, 1.158 mmol). This solution was added dropwise to a 0° C. mix ofDMF (1 ml) and 3-aminophenyl acetamide. The reaction was stirred at 0°C. for min and then at RT for 1 h. The reaction mix was diluted withEtOAc and water. The layers were separated, and the aqueous layer wasextracted twice with EtOAc. The combined organic layer was washed 3times with brine, dried over Na₂SO₄, and concentrated under reducedpressure, giving2-[3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]acetamide.

[0325] Preparation IX

[0326] 2-[3-(4-Chloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (136.5mg, 0.5177 mmol) is combined with 2-chlorobenzimidazole (86.9 mg, 0.5177mmol) and potassium carbonate (93 mg, 0.673 mmol) in AcCN (5 ml) andheated at 65-75° C. for 2 to 20 hours. The reaction mix is cooled to RTand the inorganic salts are filtered off. The AcCN solution isconcentrated down under reduced pressure. The crude is purified on asilica gel column with an EtOAc/hexane to MeOH/CH₂Cl₂ elution gradient,giving2-{3-[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}acetamide.

[0327] Preparation X

[0328] To a mixture of2-[3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]acetamide (36.6 mg,0.1388 mmol) in IpOH (1 ml) were added DIEA (27 μl, 0.1527 mmol) and3-bromoaniline (26.3 mg, 0.1527 mmol). The mix was heated at 100-120° C.for 18 h. The solution was cooled to RT and sonicated. The precipitatewas filtered and dried under reduced pressure, giving2-{3-[4-(3-bromophenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}acetamide.

[0329] Preparation XII

[0330] 2,4-Dichloro-1,3,5-triazine (405.8 mg, 2.7065 mmol) is dissolvedin DMF (2 ml). To the stirring solution cooled to 0° C. is added DIEA(471 ,μl, 2.7065 mmol). This solution is added dropwise to a 0° C. mixof DMF (2 ml) and 3-[1,2,3]triazol-1-ylmethyl-phenylamine (471.5 mg,2.7065 mmol). The reaction is stirred at 0° C. for 15 minutes to 40minutes and then at RT for 20 minutes to 2 hours. The mixture is dilutedwith EtOAc and water. The layers are separated, and the aqueous layer isextracted twice with EtOAc. The combined organic layer is washed 3 timeswith brine, dried over Na₂SO₄, and concentrated under reduced pressure,giving(4-chloro-[1,3,5]triazin-2-yl)-(3-[1,2,3]triazol-1-ylmethyl-phenyl)amineas a white foam.

[0331] Preparation XIII

[0332] 2,4-Dichloro-1,3,5-triazine (327.5 mg, 2.1845 mmol) was dissolvedin DMF (2 ml) and cooled to 0° C. To this solution were added DIEA (381μl, 2.184 mmol) and 2-chloro-benzimidazole (333.3 g, 2.1845 mmol). Thereaction mixture was kept at 0° C. for 15 min and then at RT for 45 min.The crude 2-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzimidazole wasused as is in the next step. To crude2-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzimidazole was addedDIEA (381 ul, 2.184 mmol) and then a solution of DMF (1 ml) and3-(1H-tetrazol-5-ylmethyl)phenylamine (382.7 mg, 2.1845 mmol). Thereaction was heated at 60-75° C. for 18 h. The reaction was cooled to RTand concentrated to a small volume. The crude was eluted on a silica gelcolumn with a MeOH/CH₂Cl₂ elution gradient, giving[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3-(1H-tetrazol-5-ylmethyl)-phenyl]amine.

[0333] Preparation XIV

[0334] 2,4-Dichloro-1,3,5-triazine (204 mg, 1.362 mmol) is dissolved inDMF (2 mL) and cooled to 0° C. To this solution are added DIEA (238 μl,1.362 mmol) and3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenylamine (360 mg, 1.362mmol) dissolved in DMF (2 mL). (The aniline is prepared the followingway: 2,6-dimethoxy-4-nitrophenol is prepared according to (Tepe, Med.Chem., 39, (1996); 2188-2196) and reacted via Mitsunobu with2-(l-triazolyl)ethanol (prepared according to Kume et al., Journal ofAntibiotics; (1993) 46, 177-195). The Mitsunobu product is reduced tothe aniline via Pd on carbon.) The mixture is kept at 0° C. for 15 to 30minutes and then at RT for 15 minutes to 2 hours. The reaction mix isadded to water, whereupon the compound precipitated out of solution. Theprecipitate is filtered and dried under vacuum, giving(4-chloro-[1,3,5]triazin-2-yl)-[3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenyl]amine.

[0335](4-Chloro-[1,3,5]triazin-2-yl)-[3,5-dimethoxy-4-(2-morpholin-4-yl-ethoxy)phenyl]amineand(4-chloro-[1,3,5]triazin-2-yl)-[3,4-dimethoxy-5-(morpholin-4-ylmethoxy)phenyl]aminewere prepared in a similar fashion.

[0336] Preparation XV

[0337](4-Chloro-[1,3,5]triazin-2-yl)-[3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenyl]amine(407 mg, 1.076 mmol) is combined with 2-chlorobenzimidazole (164 mg,1.076 mmol) and K₂CO₃(179 mg, 1.292 mmol) in AcCN (10 ml) and heated at65 to 75° C. for 4 to 20 hours. The mix is concentrated down underreduced pressure and treated with water. A white precipitate forms whichis filtered and dried under vacuum, giving[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3,5-dimethoxy-4-(2-[1,2,3]triazol-1-yl-ethoxy)phenyl]-amine.

[0338][4-(2-Chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3,5-dimethoxy-4-(2-morpholin-4-yl-ethoxy)phenyl]amineand[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3,4-dimethoxy-5-(2-morpholin-4-yl-ethoxy)phenyl]aminewere prepared in a similar fashion.

[0339] Preparation XVI

[0340] [3-(4-Chloro-[1,3,5]triazin-2-ylamino)phenyl]acetic acid methylester (3.530 g, 12.67 mmol) is combined with 2-chlorobenzimidazole(1.933 g, 12.67 mmol) and K₂CO₃(2.101 g, 15.20 mmol) in AcCN (50 ml) andheated at 65-750° C. for 2 to 20 hours. The reaction mix is cooled toRT. The inorganic salts are filtered off. The AcCN solution isconcentrated down under reduced pressure. The crude is purifired bychromatography with an EtOAc/hexane elution gradient, giving{3-[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-ylamino]phenyl}aceticacid methyl ester.

[0341] Similarly,4-[4-(2-chlorobenzimidazol-1-yl)-[l,3,5]triazin-2-ylamino]benzoic acidmethyl ester was prepared. MS m/3=[M+H] is 381. Calc'd for C₁₈H13ClN₆O₂:380.08.

[0342] Preparation XVII

[0343](4-Chloro-[1,3,5]triazin-2-yl)-(3-[I,2,3]triazol-1-ylmethyl-phenyl)-amine(552.7 mg, 1.921 mmol) is combined with 2-chlorobenzimidazole (381 mg,2.497 mmol) and K₂CO₃ (372 mg, 2.689 mmol) in AcCN (10 ml) and heated at65-75° C. for 2 to 20 h. The reaction mix is cooled to RT and dilutedwith MeOH and CH₂Cl₂. The inorganic salts are filtered off and theorganic solution is concentrated under reduced pressure. The crude istreated with AcCN (5-8 ml), forming a precipitate. The precipitate isfiltered and dried, giving[4-(2-chloro-benzoimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3-[1,2,3]triazol-1-ylmethyl-phenyl)-amine.

[0344] Similarly,[4-(2-chloro-imidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)aminewas prepared by reacting(4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine with2-chloroimidazole (prepared according to literature procedure: “FacileSynthesis of 2-Substituted Imidazoles”, K. L. Kirk, J. Org. Chem. 43(1978) 4381-4383). MS m/z=363 [M+H]⁺. Calc'd for Cl₁₅H₁₅ClN₆O₃: 362. 09.

[0345] Preparation XVIII

[0346] To a mixture of(4-chloro-[l,3,5]triazin-2-yl)-(3-[l,2,3]triazol-1-ylmethyl-phenyl)-amine(64.8 mg, 0.2252 mmol) in IpOH (1 ml) were added DIEA (39 ul, 0.225mmol) and 3-bromoaniline (38.7 mg, 0.2252 mmol). The mix was heated at100-120° C. for 4 to 18 h. The solution was cooled to RT and sonicated.A precipitate formed, was filtered and dried under reduced pressuregiving N-(3-bromophenyl)-N′-(3-[1,2,3]triazol-1-yl-methyl-phenyl)-[1,3,5]triazine-2,4-diamine.

[0347] Preparation XIX

[0348] 2,4-Dichloro-1,3,5-triazine (122.7 mg, 0.8182 mmol) is dissolvedin DMF (1 ml). To the stirred solution cooled to 0° C. is added DIEA(150 μl, 0.861 mmol) . This solution is added dropwise to a 0° C. mix ofDMF (2 ml), DIEA (150 μl, 0.861 mmol) and3-(1-trityl-1H-imidazol-2-ylmethyl)-phenylamine (340 mg, 0.8182mmol)(prepared from 3-nitrophenylacetonitrile to yield the imidazoline(Amemiya et al, J. Med. Chem., (1992) 35, 750-755), which is oxidized tothe imidazole (Amemiya et al.; Synthetic Communications, 20 2483-2489),trityl-protected and reduced from nitro to amine) . The reaction isstirred at 0° C. for 15 minutes to 40 minutes and then at RT for 20minutes to 2 h. The reaction mix is diluted with EtOAc and water. Thelayers are separated, and the aqueous layer is extracted twice withEtOAc. The combined organic layer is washed 3 times with brine, driedover Na₂SO₄, and concentrated under reduced pressure. The crude iseluted on a silica gel column with EtOAc/hexane (1:1), giving(4-chloro-[1,3,5]triazin-2-yl)-[3-(l-trityl-1H-imidazol-2-ylmethyl)phenyl]amine.

[0349] Preparation XX

[0350](4-Chloro-[1,3,5]triazin-2-yl)-[3-(l-trityl-1H-imidazol-2-ylmethyl)phenyl]amine(331 mg, 0.6256 mmol) is combined with 2-chlorobenzimidazole (114.6 mg,0.7508 mmol) and K₂CO₃ (190 mg, 1.376 mmol) in AcCN (5 ml) and heated at65-75° C. for 2 to 20 h. The reaction mix is cooled to RT. The productprecipitates out of AcCN, and is filtered off. The crude solid istreated with water, filtered and dried, giving[4-(2-chloro-benzoimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3-(1-trityl-1H-imidazol-2-ylmethyl)phenyl]amine.

[0351] Preparation XXI

[0352] A mixture of the compound 2,4-dichloro-1,3,5-triazine (2.5 g,16.7 mmol) and solid K₂CO₃ (6.9g, 49.9 mmol) was suspended in AcCN (50mL) under nitrogen at 0° C. followed by addition ofN-methyl-3-chloroaniline (2.5 g, 17.7 mmol). The mixture was stirred at0° C. for 2 h. The reaction was quenched by pouring onto ice/water. Thewhite solid formed was collected by suction filtration and dried undervacuum to give N-methyl-2-chloro-4-(3-chloroanilino)-1,3,5-triazine. MSm/z=256. Calc'd for C₁₀H₈Cl₂N₄: 254.01.

[0353] Similarly, (3-chlorophenyl)-(4-chloro-[1,3,5]triazin-2-yl)aminewas prepared from 3-chloroaniline and 2,4-dichloro-1,3,5-triazine.

[0354] Preparation XXII

[0355] To a mixture of(3-chloro-4-fluoro-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (1.7 g,6.56 mmol) and MeI (1.5 mL) in DMF (20 mL) under a nitrogen atmospherewas added NaH (60% dispersion, 0.53 mg, 13.3 mmol). The mixture wasstirred for 3 h. The reaction was quenched by the addition of water andthe organic extracts are taken up in EtOAc, dried over anh. MgSO₄ andconcentrated under reduced pressure. The crude product was purified viamedium pressure liquid chromatography using CH₂Cl₂ as the solvent systemto give N-methyl-2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine.

[0356] Similarly,allyl-(3-chloro-4-fluoro-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-aminewas prepared from allyl bromide and2-chloro-4-(3-chloroanilino)-1,3,5-triazine. Similarly,N-ethyl-2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine is preparedfrom ethyl iodide and 2-chloro-4-(3-chloroanilino)-1,3,5-triazine.

[0357] Preparation XXIII

[0358] 2,4-Dichloro-1,3,5-triazine (12.6 g, 84 mmol) was dissolved inDMF (100 mL) under N₂ and cooled to 0° C. DIEA (11.7 g, 90 mmol) wasadded, followed by 4-aminoveratrole (13.35 g, 87 mmol). The reactionsolution was stirred with gradual warming to RT. The reaction wasquenched after 3.5 h with water, which causes a gray precipitate toform. This precipitate was recovered by vacuum filtration, washed withcold water, dried under high vacuum, then eluted through a 28×4.5 cmcolumn of silica gel (0.1% NH₄OH buffered 1%, 2%, 3%, 4%, and 5%MeOH/CH₂Cl₂ step gradient) giving(4-chloro-[1,3,5]triazin-2-yl)-(3,4-dimethoxy-phenyl)-amine as an offwhite solid.

[0359] Preparation XXIV

[0360] 4-Chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (300mg, 1 mmol) was dissolved in hydrazine monohydrate (0.63 mL, 20 mmol)and heated at 120° C. for 25 min. The resulting white solid was filteredand dried to provide(4-hydrazino-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine.(4-Hydrazino-[l,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine (40mg,0.14 mmol) was reacted with benzoyl acetonitrile (20 mg, 0.14 mmol) inrefluxing absolute EtOH (1 mL). The resulting[4-(5-amino-4-phenyl-pyrazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-aminewas purified by silica gel chromatography. MS m/z=442 [M+Na]⁺. Calc'dfor C₂₁H₂₁N₇O ₃: 419.17.

[0361] The related regioisomer,[4-(5-amino-3-phenyl-pyrazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine,was prepared as above by using formyl phenylacetonitrile as thecondensing reagent. MS m/z=442[M+Na]⁺. Calc'd for C₂₁H₂₁N₇O₃: 419.17.

[0362] Preparation XXV

[0363] 7-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline (440 mg, 2.2mmol) was dissolved in DMF (10 mL) under N₂ at RT. DIEA (284 mg, 2.2mmol) was added, and the reaction solution was cooled to 0° C.2,4-Dichloro-1,3,5-triazine was added, and reaction was stirred withgradual warming to RT. The reaction was quenched after 3 h with water,which caused a fine precipitate to form, which is not filterable. Thismixture was extracted 3 times with EtOAc. The EtOAc extracts were washedbrine, combined, dried over Na₂SO₄, filtered, concentrated, and driedunder high vacuum giving1-(4-chloro-[1,3,5]triazin-2-yl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinolineas a yellow oil that was used without further purification.

[0364] Preparation XXVI

[0365] 2,4-Dichloro-1,3,5-triazine (1.95 g, 13 mmol) was dissolved inDMF (50 mL) under N₂ and cooled to 0° C. DIEA (1.68 g, 13 mmol) wasadded, followed by the addition of 6-methyl-1,2,3,4-tetrahydroquinoline(1.91 g, 13 mmol). The reaction was stirred with gradual warming to RT.The reaction was quenched after 3 h with water, which caused a stickyprecipitate to form. The mixture was extracted 3 times with EtOAc. TheEtOAc extracts were washed brine, combined, dried over Na₂SO₄, filtered,and concentrated, then dried under high vacuum to remove residual tracesof DMF. The recovered material was purified by silica gel chromatography(5%, 10%, 20% and 40% EtOAc/Hexane step gradient) giving1-(4-chloro-[1,3,5]triazin-2-yl)-6-methyl-1,2,3,4-tetrahydro-quinolineas a white solid.

[0366] Preparation XXVII

[0367] 2,4-Dichloro-1,3,5-triazine (3 g, 20 mmol) was dissolved in DMF(20 mL) under N₂ and cooled to 0° C. DIEA (2.58 g, 20 mmol) was added,followed by 3-chloro-6-methylaniline (2.83 g, 20 mmol). The reactionsolution was stirred with gradual warming to RT. The reaction wasquenched after 3 h with water, then extracted 3 times with EtOAc. TheEtOAc extracts were washed with brine, combined, dried over Na₂SO₄,filtered, and concentrated. The crude was purified by silica gelchromatography (25%, 40%, 60% EtOAc/Hexane step gradient) giving(5-chloro-2-methyl-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-amine as awhite solid.

[0368] Preparation XXVIII

[0369] The compounds below were prepared according to the procedure forExample 2, Steps 4 and 5, below, substituting the appropriate amines ineach of the two reaction steps:

[0370]3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzonitrile;

[0371]1-(3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-phenyl)-ethanone;

[0372]{4-[2-(4-chloro-2-methyl-phenylamino)-pyridin-3-yl]-[1,3,5]triazin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine;

[0373](3,4,5-trimethoxy-phenyl)-[4-(2-vinylamino-pyridin-3-yl)-[1,3,5]triazin-2-yl]-amine;

[0374]N1-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-yl}-propane-1,3-diamine;

[0375]3-{3-[4-(3,4,5-Trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzamide;and

[0376][4-(2-amino-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine.

[0377] Preparation XXIX

[0378] Oxindole (176 mg, 1.32 mmol) was dissolved in a 1:1 mixture ofTHF:DMF (4 mL), under N₂, at RT. NaH (53 mg of a 60% suspension inmineral oil, 1.32 mmol) was added, which produced a vigorous gasevolution. This mixture was stirred for 30 min at RT, then(4-chloro-[l,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (156 mg,0.53 mmol) was added and the reaction was heated to 80° C. for 2 h. Thereaction was cooled to RT, partially concentrated under reducedpressure, diluted with EtOAc, then extracted with water. The waterextract was back extracted two times with fresh EtOAc. All of the EtOAcextracts were washed with brine, combined, dried over NaSO₄, filteredand concentrated. The recovered material was purified by preparativeHPLC(5 to 100% CH₃CN:H₂O (0.1% TFA buffer) over 10 min at 20 mL/min)Crystals formed in the recovered eluant, which were recovered by vacuumfiltration, washed with water, and dried under high vacuum giving3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-indol-2-olas a yellow solid: MS m/z=394 [M+H]⁺. Calc'd for C₂₀H₁₉N₅O₄: 393.14.

[0379] Similarly,1-methyl-3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-indol-2-olwas prepared from(4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (130 mg,0.44 mmol) was reacted with N-methylindolin-2-one (162 mg, 1.1 mmol,prepared according to the procedure of Bordwell and Fried, J. Org.Chem., (1991) 56, 4218-4223, as a yellow solid: MS m/z=408 [M+H]⁺.Calc'd for C₂₁H₂₁N₅O₄: 407.16.

[0380] Similarly5-chloro-3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-indol-2-olwas prepared from(4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (134 mg,0.45 mmol) and 5-chloro-oxindole (189 mg, 1.1 mmol) giving a yellowsolid: MS m/z=428 [M+H]⁺. Calc'd for C₂₀H₁₈ClN₅O₄: 427.10.

[0381] Preparation XXX

[0382] A mixture of[4-(2-chloro-benzimidazol-1-yl)-[l,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine(Example 1, step 1)(41 mg, 0.10 mmol), 3-aminobenzamide (14 mg, 0.10mmol) and DIEA (16 mg, 0.12 mmol) in IpOH (3.5 mL) was heated at100-130° C. for 10-40h. On cooling a precipitate formed which wascollected, washed with IpOH, ether and dried to give3-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-ylamino}-benzamideas a yellow solid.

[0383] Compounds below were synthesized according to the procedureoutlined above, substituting the appropriate reagents:

[0384]4-{l-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-ylamino}-benzonitrile;

[0385]2-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-ylamino}-benzamide;

[0386]3-{l-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-ylamino}-benzoicacid methyl ester;

[0387]3-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-ylamino}-benzoicacid;

[0388](1H-indazol-6-yl)-{l-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-yl}-amine;

[0389](1H-indazol-5-yl)-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-yl}-amine;

[0390](3-nitrobenzyl)-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-yl}-amine;

[0391](4-bromobenzyl)-{l-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-yl}-amine;

[0392](3-bromobenzyl)-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-yl}-amine;and

[0393](4-nitrobenzyl)-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-yl}-amine.

[0394] Preparation XXXI

[0395] The compounds below were prepared according to the procedure forExample 1, Step 1, below, substituting the appropriate benzimidazole:

[0396][4-(2-chloro-5-methoxy-benzoimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine;and

[0397][4-(2-chloro-6-methoxy-benzoimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine.

[0398] Preparation XXXII

[0399] 2,4-Dichloro-1,3,5-triazine (89.1 mg, 0.5944 mmol) was dissolvedin DMF (0.5 ml) and cooled to 0° C. To this solution were added DIEA(104 μl), 4-methoxy-3-(2-methoxy-ethoxy)phenylamine (TFA salt)(264 mg,˜0.59 mmol) and DIEA (208 μl) in DMF (1 ml). The reaction mixture waskept at 0° C. for 15 to 30 min and then at RT for 15 min to 2 h. Thereaction mixture was diluted with EtOAc and washed with brine. Theorganic layer was dried over Na₂SO₄, filtered, and evaporated in vacuo,to give(4-chloro-[1,3,5]triazin-2-yl)-[4-methoxy-3-(2-methoxy-ethoxy)-phenyl]amine.

[0400] Preparation XXXIII

[0401] 1143 (43 mg, 0.2862 mmol) was dissolved in 0.5 ml DMF and cooledto 0° C. DIEA (0.05 ml) was added to the solution. After 5 min thissolution was added dropwise to a solution of 3-aminophenylacetamide (43mg =0.2862 mmol) in 0.5 ml DMF at 0° C. The solution was stirred at 0°C. for 15 min and then at RT for 1 h. To the crude intermediate wasadded additional DIEA (0.050 ml) and 2-aminobenzimidazole (38 mg, 0.2862mmol). The mix was heated at 100-120° C. for 18 h. The reaction wascooled to RT and diluted with EtOAc. The organic phase was washed withH₂O and brine, dried over Na₂SO₄, and concentrated down under reducedpressure. The crude was eluted on 2×1.0 mm silica gel prep plates with5% MeOH/CH₂Cl₂. The major band was extracted with 15% MeOH/CH₂Cl₂,yielding.2-{3-[4-(2-amino-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-acetamide.MS m/z=361 [M+H] Calc'd for C₁₈H16N₈O: 360.14

[0402] The following compounds are prepared according to the aboveprocedure.

[0403]2-{3-[4-(2-Amino-benzoimidazol-1-yl)-[I,3,5]triazin-2-ylamino]-phenyl}-N-pyridin-2-ylmethyl-acetamide.MS m/z=452 [M+H] Calc'd for C₂₄H₂₁N₉O: 451.19

[0404]1-[4-(3-[1,2,3]Triazol-1-ylmethyl-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzoimidazol-2-ylamine.MS m/z=385 MS m/z=385 [M+H] Calc'd for C₁₉H₁₆N₁0: 384.16

EXAMPLE 1

[0405]

[0406]N-(4-Phenoxyphenyl)-3-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzimidazo-1-2-ylamino}benzamide

[0407] Step 1

[0408] Preparation of[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine

[0409] To a suspension of(4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (2.97 g,10 mmol) and 2-chlorobenzimidazole (1.53 g, 10 mmol) in dry AcCN (100mL) was added ground K₂CO₃ (1.68 g, 12 mmol). The resulting mixture washeated at 65° C. for 4 h, cooled to RT, concentrated in vacuo andpurified by column chromatography (EtOAc/n-Hexanes) to provide[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amineas a white powder. MS m/z 413=[M+H]⁺. Calc'd for C₁₉H₁₇ClN6O₃: 412.11:

[0410] Step 2.

[0411] Preparation ofN-(4-phenoxyphenyl)-3-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzimidazo-1-2-ylamino}benzamide

[0412] To 96 mg (0.23 mmol) of[4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine(Step 1) were added 3-amino-N-(4-phenoxyphenyl)benzamide (74.3 mg, 0.24mmol), DIEA (0.061 ml), and IpOH (2 ml). The mixture was heatedovernight in a sealed tube at 100° C. The reaction mixture was cooled toRT, diluted with CH₂C₁ ₂, and washed with 2N HCl, water, and then brine.The organic layer was dried over Na₂SO₄ and filtered. Upon sitting at RTfor several hours, a white solid precipitated out of CH₂Cl₂. The solidwas filtered and dried, yielding the product. MS m/z 681=[M+H]⁺. Calc'dfor C₃₈H₃₂N₈O5: 680.722.

[0413] EXAMPLE 2A

[0414]N-(4-Chlorophenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzamide

[0415] EXAMPLE 2B

[0416]N-(Phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide

[0417] Step 1

[0418] Preparation of 2-chloro-nicotinamidine

[0419] 2-Chloro-3-cyanopyridine (5.0 g, 36 inmol) was dissolved in dryEtOH (100 mL) at 0° C. HCl was bubbled through the mixture for 3 h andthe mixture was sealed and refrigerated (about 8° C.) overnight. Afterconcentration, the residue was stirred with ammonium acetate (5.5 g) in100 mL IpOH. After 12 h, the pH was adjusted to 9 (from 4) usingconcentrated NH₄OH solution, and stirring continued two more days. Themixture was concentrated and purified by flash chromatography (10:1:0.1CH₂Cl₂/MeOH/NH₄OH). Trituration in hot tBuOMe/IpOH removed some residualamide side-product to provide the amidine, 2-chloro-nicotinamidine as awhite solid.

[0420] Step 2

[0421] Preparation of amino-(2-chloro-pyridin-3-yl)-methylcyanamide

[0422] 2-Chloro-nicotinamidine (Step 1) was suspended in 10 mL IpOH with500 mg solid cyanamide and the stirring solids were dissolved byaddition of 5% aqueous NaHCO₃ (30 mL). After two days stirring, theamino-(2-chloro-pyridin-3-yl)-methylcyanamide was isolated by EtOAcextraction of the aqueous reaction mixture followed by flashchromatography using 95:5:0.5 CH₂Cl₂/MeOH/NH₄OH. MS m/z=181 [M+H]⁺.Calc'd for C₇H₆N₄Cl:181.03.

[0423] Step 3

[0424] Preparation of 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine

[0425] Amino-(2-chloro-pyridin-3-yl)-methylcyanamide (Step 2)(3.5 g) wasadded as a solid to a stirring, 0° C. solution of POCl₃ (2.3 ml, 25mmol) and DMF (1.9 ml, 25 mmol) in 100 ml AcCN. The clear solution wasstirred at RT for 1 h, concentrated, and immediately filtered through aplug of silica. Concentration provided2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine as a white solid. MSm/z=227 [M+H]⁺. Calc'd for C₈H₄Cl₂N₄: 225.98.

[0426] Step 4

[0427] Preparation of[4-(2-chloro-pyridin-3-yl)-_[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine

[0428] 2-Chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (1.7 g, 7.5mmol) was stirred overnight at RT with 3,4,5-trimethoxyaniline (1.5 g,8.3 mmol) in IpOH (200 mL). After addition of Et₃N (2 ml), stirring wascontinued for an additional day. The mixture was concentrated,triturated with t-BuOMe and filtered, rinsing with a small amount ofIpOH. The[4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine(2.5 g) was isolated as the Et₃HN+C₁- salt. Part of this material wasfiltered through a plug of silica and analyzed. MS m/z=374 [M+H]⁺; 3H).Calc'd for C₁₇H₁₆ClN₅O₃: 373.09. Remaining material was used withoutfiltering in the next step.

[0429] Step 5

[0430] Preparation ofN-(phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamideandN-(4-chloro-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide

[0431] To[4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine(Step 4)(94 mg, 0.25 mmol) was added 3-amino-N-(4-chlorophenyl)benzamide(185 mg, 0.74 mmol) in 150 ml DMSO, and the mixture was stirredovernight at 90-95° C. The resulting crude mixture contained an impurityoriginating from a side product in the aniline starting material. Thematerial was purified by silica gel chromatography [1:1:1hexanes/CH₂Cl₂/t-BuOMe with ramping 10:1 MeOH/NH₄OH], and thentriturated in a EtOAc/MeOH mixture and filtered to obtain a yellowsolid, a 10:1 mixture of the two compounds:

[0432]N-(4-Chloro-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide:MS m/z 584.5 [M+H]⁺. Calc'd for C₃₀H₂₆ClN₇O₄: 583.17.

[0433]N-phenyl-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide:MS m/z 550.3=[M+H]⁺. Calc'd for C₃₀H₂₇N₇O₄: 549.21.

EXAMPLE 3

[0434]

[0435]N-(4-Phenoxy-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzamide

[0436] To[4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine(Example 2, Step 4)(103 mg, 0.275 mmol) was added3-amino-N-(4-phenoxyphenyl)-benzamide (297 mg, 0.975 mmol) and DMSO (150ml), and the mixture was heated overnight at 90° C. The residue wastreated with IpOH and MeOH, triturated, sonicated, and filtered toobtainN-(4-phenoxy-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamideas a yellow solid: MS m/z 642.5 [M+H]⁺. Calc'd for C₃₆H₃₁N₇O₅: 641.24.

EXAMPLE 4

[0437]

[0438]3-[3-(4-Amino-[1,3,5]triazin-2-yl)-pyridin-2-ylamino]-N-(4-phenoxy-phenyl)benzamide

[0439][4-(2-Chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine(Example 2, Step 4)(247 mg, 1.08 mmol) was suspended in a 2 M solutionof NH₃ in IpOH (3 ml)(Aldrich), and the reaction mixture was stirredovernight in a sealed tube. Concentration, trituration in a small amountof MeOH, and filtration provided a white solid. A portion of thismaterial (97 mg, 0.47 mmol) was mixed with3-amino-N-(4-phenoxyphenyl)benzamide (320 mg, 0.96 mmol) and DMSO (250ml), and stirred overnight at 90° C. The dark residue was diluted withIpOH, sonicated, triturated, and then concentrated. Upon dilution withIpOH, a light green solid was isolated by filtration. MS m/z=476.5.[M+H]⁺. Calc'd for C₂₇H₂₁N₇O₂: 475.18.

EXAMPLE 5

[0440]

[0441] 3-[3-(4-Amino-[1,3,5]triazin-2-yl)-pyridin-2-ylamino]-N-(3-isopropyl-phenyl)-benzamide

[0442]3-[3-(4-Amino-[I,3,5]triazin-2-yl)-pyridin-2-ylamino]-N-(3-isopropyl-phenyl)-benzamidewas prepared in the same manner as Example 4. MS m/z=426.2 [M+H]. Calc'dfor C₂₄H₂₃N₇O: 425.20.

[0443] Other compounds included in this invention are set forth inTables 1-2 below. TABLE 1

# R² R^(1a)  6. amino- 4-chlorophenyl  7. amino- 3-isoquinolinyl  8.amino- 2-quinolinyl  9. amino- 2-benzthiazolyl 10. amino-2-benzimidazolyl 12. amino- 4-benzimidazolyl 13. amino- 5-benzimidazolyl14. amino- 6-benzimidazolyl 15. amino- 7-benzimidazolyl 16. amino-2-chlorophenyl 17. Br 3-isoquinolinyl 18. Br 2-quinolinyl 19. Br2-benzthiazolyl 20. Br 2-benzimidazolyl 21. Cl 4-benzimidazolyl 22. Cl5-benzimidazolyl 23. Cl 6-benzimidazolyl 24. Cl 7-benzimidazolyl 25. Cl4-chlorophenyl 26. hydroxy- 4-chlorophenyl 27. amino- 4-chlorophenyl #R² R 28. 4-phenoxyphenyl amino 29. 3-phenoxyphenyl methoxy 30.4-biphenyl methoxy 31. 4-cyclohexylphenyl methoxy 32. 2-quinolyl methoxy33. 3-isoquinolyl methoxy 34. 3-quinolyl methoxy 35. 1-isoquinolylmethoxy 36. 5-quinolyl methoxy 37. 5-isoquinolyl methoxy 38. 6-quinolylmethoxy 39. 6-isoquinolyl methoxy 40. 7-quinolyl methoxy 41.7-isoquinolyl hydroxy 42. 4-quinolyl hydroxy 43. 4-isoquinolyl hydroxy44. 4-pyridyl hydroxy 45. 4-pyrimidinyl hydroxy 46. 2-pyrimidinylhydroxy 47. 6-pyrimidinyl hydroxy 48. 4-pyridazinyl hydroxy 49.5-pyridazinyl hydroxy 50. 4-indolyl hydroxy 51. 5-isoindolyl CH₃ 52.5-naphthyridinyl CH₃ 53. 6-quinozalinyl 3-amino 54. 6-isoquinolyl CH₃55. 4-naphthyridinyl CH₃ 56. 5-quinozalinyl CH₃O 57. 4-naphthyridinylCH₃ 58. 3,4-dichlorophenyl CH₃ 59. 6-isoquinolyl CH₃ 60. 4-chlorophenylCH₃ 61. 4-chlorophenyl CH₃ 62. 6-indazolyl hydroxymethyl 63.6-isoindolyl hydroxymethyl 64. 5-indazolyl hydroxymethyl 65.5-isoindolyl hydroxymethyl 66. 6-benzothienyl hydroxymethyl 67.6-benzofuryl hydroxymethyl 68. 5-benzothienyl hydroxymethyl 69.5-benzofuryl hydroxymethyl 70. 2-benzimidazolyl hydroxymethyl 71.2-benzoxazolyl hydroxymethyl 72. 6-benzimidazolyl hydroxymethyl 73.6-benzoxazolyl hydroxymethyl 74. 6-benzthiazolyl Cl 75. 2-quinazolinylhydroxymethyl 76. 4-tertbutylphenyl Cl 77. 4-cyclohexyloxyphenyl Cl 78.4-(3-thienyl)phenyl Br 79. 4-(pyrazol-3-yl)phenyl amino 80. 4-pyridyl Cl81. 3-methoxyphenyl Cl 82. 4-sec-butylphenyl Cl 83. 4-isopropylphenyl Br

[0444] TABLE 2

# R² R^(1a)  84. 4-amino- 4-chlorophenyl  85. 4-amino- 3-isoquinolinyl 86. 4-amino- 2-quinolinyl  87. 4-amino- 2-benzthiazolyl  88. 4-amino-2-benzimidazolyl  89. 4-amino- 4-benzimidazolyl  90. 4-amino-5-benzimidazolyl  91. 4-amino- 6-benzimidazolyl  92. 4-amino-7-benzimidazolyl  93. Br 2-chlorophenyl  94. Br 3-isoquinolinyl  95. Br2-quinolinyl  96. Br 2-benzthiazolyl  97. Br 2-benzimidazolyl  98. Br4-benzimidazolyl  99. Br 5-benzimidazolyl 100. Br 6-benzimidazolyl 101.Br 7-benzimidazolyl 102. Br 4-chlorophenyl 103. hydroxy 4-chlorophenyl104. phenyl 4-chlorophenyl # R^(1a) R² 105. 4-phenoxyphenyl H 106.3-phenoxyphenyl methoxy 107. biphenyl methoxy 108. 4-cyclohexylphenylmethoxy 109. 2-quinolyl methoxy 110. 6-benzothienyl hydroxymethyl 111.6-benzofuryl hydroxymethyl 112. 4-tertbutylphenyl Cl 113. 4-propylphenylBr 114. 4-isopropylphenyl Cl 115. 4-isobutylphenyl phenyl 116.4-sec-butylphenyl amino

[0445] Although the pharmacological properties of the compounds ofFormula I vary with structural change, in general, activity possessed bycompounds of Formula I may be demonstrated in vivo. The pharmacologicalproperties of the compounds of this invention may be confirmed by anumber of pharmacological in vitro assays. The exemplifiedpharmacological assays which follow have been carried out with thecompounds according to the invention and their salts. Compounds of thepresent invention showed inhibition of KDR kinase at doses less than 50μm.

BIOLOGICAL EVALUATION HtEC Proliferation Assay

[0446] Human Umbilical Vein Endothelial cells are purchased fromClonetics, Inc., as cryopreserved cells harvested from a pool of donors.These cells, at passage 1, are thawed and expanded in EBM-2 completemedium, until passage 2 or 3. The cells are trypsinized, washed inDMEM+10% FBS+antibiotics, and spun at 1000 rpm for 10 min. Prior tocentrifugation of the cells, a small amount is collected for a cellcount. After centrifugation, the medium is discarded, and the cells areresuspended in the appropriate volume of DMEM+10% FBS+antibiotics toachieve a concentration of 3×10⁵ cells/mL. Another cell count isperformed to confirm the cell concentration. The cells are diluted to3×10⁴ cells/mL in DMEM+10% FBS+antibiotics, and 100 μL of cells areadded to a 96-well plate. The cells are incubated at 37° C. for 22 h.

[0447] Prior to the completion of the incubation period, compounddilutions are prepared. Five-point, five-fold serial dilutions areprepared in DMSO, at concentrations 400-fold greater than the finalconcentrations desired. 2.5 μL of each compound dilution are dilutedfurther in a total of 1 mL DMEM+10% FBS+antibiotics (400× dilution).Medium containing 0.25% DMSO is also prepared for the 0 μM compoundsample. At the 22-hour timepoint, the medium is removed from the cells,and 100 μL of each compound dilution is added. The cells are incubatedat 37° C. for 2-3 h.

[0448] During the compound pre-incubation period, the growth factors arediluted to the appropriate concentrations. Solutions of DMEM+10%FBS+antibiotics, containing either VEGF or bFGF at the followingconcentrations: 50, 10, 2, 0.4, 0.08, and 0 ng/mL are prepared. For thecompound-treated cells, solutions of VEGF at 550 ng/mL or bFGF at 220ng/mL for 50 ng/mL or 20 ng/mL final concentrations, respectively, areprepared since 10 μL of each will be added to the cells (110 μL finalvolume). At the appropriate time after adding the compounds, the growthfactors are added. VEGF is added to one set of plates, while bFGF isadded to another set of plates. For the growth factor control curves,the media on wells B4-G6 of plates 1 and 2 are replaced with mediacontaining VEGF or bFGF at the varying concentrations (50-0 ng/mL). Thecells are incubated at 37° C. for an additional 72 h.

[0449] At the completion of the 72 h incubation period, the medium isremoved, and the cells are washed twice with PBS. After the second washwith PBS, the plates are tapped gently to remove excess PBS, and thecells are placed at −70° C. for at least 30 min. The cells are thawedand analyzed using the CyQuant fluorescent dye (Molecular ProbesC-7026), following the manufacturer's recommendations. The plates areread on a Victor/Wallac 1420 workstation at 485 nm/530 nm(excitation/emission). Raw data are collected and analyzed using a4-parameter fit equation in XLFit. IC₅₀ values are then determined.

Angiogenesis Model

[0450] To determine the effects of the present compounds on angiogenesisin vivo, selective compounds are tested in the rat cornealneovascularization micropocket model or the angiogenesis assay ofPassaniti, Lab. Invest., 67, 519-28 (1992).

Rat Corneal Neovascularization Micropocket Model

[0451] In Life Aspects

[0452] Female Sprague Dawley rats weighing approximately 250 g wererandomized into one of five treatment groups. Pretreatment with thevehicle or compound was administered orally, 24 h prior to surgery andcontinued once a day for seven additional days. On the day of surgery,the rats were temporarily anesthetized in an Isofluorane gas chamber(delivering 2.5 liters/min oxygen +5% Isofluorane). An othoscope wasthen placed inside the mouth of the animal to visualize the vocal cords.A tip-blunted wire was advanced in between the vocal cords and used as aguide for the placement of an endotracheal Teflon tube (Small Parts Inc.TFE-standard Wall R-SWTT-18). A volume-controlled ventilator (HarvardApparatus, Inc. Model 683) was connected to the endotracheal tube todeliver a mixture of oxygen and 3% Isofluorane. Upon achieving deepanesthesia, the whiskers were cut short and the eye areas and eyesgently washed with Betadine soap and rinsed with sterile saline. Thecorneas were irrigated with one to two drops of Proparacaine HClophthalmic topical anesthetic solution (0.5%)(Bausch and LombPharmaceuticals, Tampa Fla.). The rat was then positioned under thedissecting microscope and the corneal surface brought into focus. Avertical incision was made on the midline of the cornea using a diamondblade knife. A pocket was created by using fine scissors to separate theconnective tissue layers of the stroma, tunneling towards the limbus ofthe eye. The distance between the apex of the pocket and the limbus wasapproximately 1.5 mm. After the pocket had been made, the soakednitrocellulose disk filter (Gelman Sciences, Ann Arbor Mich.) wasinserted under the lip of the pocket. This surgical procedure wasperformed on both eyes. rHu-bFGF soaked disks were placed into the righteye, and the rHu-VEGF soaked disks were placed into the left eye.Vehicle soaked disks were placed in both eyes. The disk was pushed intoposition at the desired distance from the limbal vessels. Ophthalmicantibiotic ointment was applied to the eye to prevent drying andinfection. After seven days, the rats were euthanized by CO₂asphyxiation, and the eyes enucleated. The retinal hemisphere of the eyewas windowed to facilitate fixation, and the eye placed into formalinovernight.

[0453] Post Mortem Aspects

[0454] After twenty-four hours in fixative, the corneal region ofinterest was dissected out from the eye, using fine forceps and arazorblade. The retinal hemisphere was trimmed off and the lensextracted and discarded. The corneal dome was bisected and thesuperfluous cornea trimmed off. The iris, conjunctiva and associatedlimbal glands were then carefully teased away. Final cuts were made togenerate a square 3×3 mm containing the disk, the limbus, and the entirezone of neovascularization.

[0455] Gross Image Recording

[0456] The corneal specimens were digitally photographed using a SonyCatsEye DKC₅₀₀₀ camera (A. G. Heinz, Irvine Calif.) mounted on a NikonSMZ-U stereo microscope (A. G. Heinz). The corneas were submerged indistilled water and photographed via trans-illumination at approximately5.0 diameters magnification.

[0457] Image Analysis

[0458] Numerical endpoints were generated using digital micrographscollected from the whole mount corneas after trimming and were used forimage analysis on the Metamorph image analysis system (Universal ImagingCorporation, West Chester Penn.). Three measurements were taken: Diskplacement distance from the limbus, number of vessels intersecting a 2.0mm perpendicular line at the midpoint of the disk placement distance,and percent blood vessel area of the diffusion determined bythresholding.

[0459] General Formulations

[0460] 0.1% BSA in PBS Vehicle

[0461] 0.025 g of BSA was added to 25.0 ml of sterile 1× phosphatebuffered saline, gently shaken until fully dissolved, and filtered at0.2 μm. Individual 1.0 ml samples were aliquoted into 25 single usevials, and stored at −20° C. until use. For the rHu-bFGF disks, a vialof this 0.1% BSA solution was allowed to thaw at room temperature. Oncethawed, 10 μl of a 100 mM stock solution of DTT was added to the 1 mlBSA vial to yield a final concentration of 1 mM DTT in 0.1% BSA.

[0462] rHu-VEGF Dilutions

[0463] Prior to the disk implant surgery, 23.8 μl of the 0.1% BSAvehicle above was added to a 10 μg rHu-VEGF lyophilized vial yielding afinal concentration of 10 μM.

[0464] rHu-bFGF

[0465] Stock concentration of 180 ng/μl

[0466] R&D rHu-bFGF

[0467] Added 139 μl of the appropriate vehicle above to the 25 μg viallyophilized vial. 13.3 μl of the [180 ng/μl] stock vial and added 26.6μl of vehicle to yield a final concentration of 3.75 μM concentration.

[0468] Nitro-cellulose Disk Preparation

[0469] The tip of a 20-gauge needle was cut off square and beveled withemery paper to create a punch. This tip was then used to cut out ≅0.5 mmdiameter disks from a nitrocellulose filter paper sheet (GelmanSciences). Prepared disks were then placed into Eppendorf microfugetubes containing solutions of either 0.1% BSA in PBS vehicle, 10 μMrHu-VEGF (R&D Systems, Minneapolis, Minn.), or 3.75 μM rHu-bFGF (R&DSystems, Minneapolis, Minn.) and allowed to soak for 45-60 min beforeuse. Each nitrocellulose filter disk absorbs approximately 0.1 μl ofsolution.

[0470] In the rat micropocket assay, compounds of the present inventionwill inhibit angiogenesis at a dose of less than 50 mg/kg/day.

Tumor Model

[0471] A431 cells (ATCC) are expanded in culture, harvested and injectedsubcutaneously into 5-8 week old female nude mice (CD1 nu/nu, CharlesRiver Labs)(n=5-15). Subsequent administration of compound by oralgavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumorcell challenge and generally continues either once or twice a day forthe duration of the experiment. Progression of tumor growth is followedby three dimensional caliper measurements and recorded as a function oftime. Initial statistical analysis is done by repeated measures analysisof variance (RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control.Compounds of the present invention are active at doses less than 150mpk.

Rat Adjuvant Arthritis Model

[0472] The rat adjuvant arthritis model (Pearson, Proc. Soc. Exp. Biol.91, 95-101 (1956)) is used to test the anti-arthritic activity ofcompounds of the formula 1, or salts thereof. Adjuvant Arthritis can betreated using two different dosing schedules: either (i) starting timeof immunization with adjuvant (prophylactic dosing); or from day 15 whenthe arthritic response is already established (therapeutic dosing).Preferably a therapeutic dosing schedule is used.

Rat Carrageenan-induced Analgesia Test

[0473] The rat carrageenan analgesia test was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated aspreviously described for the Carrageenan Foot Pad Edema test. Threehours after the injection of the carrageenan, the rats were placed in aspecial plexiglass container with a transparent floor having a highintensity lamp as a radiant heat source, positionable under the floor.After an initial twenty minute period, thermal stimulation was begun oneither the injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its footwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined.

[0474] Pharmaceutical compositions of this invention comprise a compoundof the formulas described herein or a pharmaceutically acceptable saltthereof; an additional agent selected from a kinase inhibitory agent(small molecule, polypeptide, antibody, etc.), an immunosuppressant, ananticancer agent, an anti-viral agent, antiinflammatory agent,antifungal agent, antibiotic, or an anti-vascular hyperproliferationcompound; and any pharmaceutically acceptable carrier, adjuvant orvehicle. Alternate compositions of this invention comprise a compound ofthe formulas described herein or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.Such compositions may optionally comprise one or more additionaltherapeutic agents, including, for example, kinase inhibitory agents(small molecule, polypeptide, antibody, etc.), immunosuppressants,anti-cancer agents, anti-viral agents, antiinflammatory agents,antifungal agents, antibiotics, or anti-vascular hyperproliferationcompounds.

[0475] The term “pharmaceutically acceptable carrier or adjuvant” refersto a carrier or adjuvant that may be administered to a patient, togetherwith a compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

[0476] Pharmaceutically acceptable carriers, adjuvants and vehicles thatmay be used in the pharmaceutical compositions of this inventioninclude, but were not limited to, ion exchangers, alumina, aluminumstearate, lecithin, self-emulsifying drug delivery systems (SEDDS) suchas d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

[0477] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich were commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, were also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions wereadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

[0478] The pharmaceutical compositions of this invention may compriseformulations utilizing liposome or microencapsulation techniques. Suchtechniques were known in the art.

[0479] The pharmaceutical compositions of this invention may beadministered by nasal aerosol or inhalation. Such compositions wereprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

[0480] Formulations

[0481] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I in associationwith one or more non-toxic, pharmaceutically-acceptable carriers and/ordiluents and/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. The activecompounds of the present invention may be administered by any suitableroute, preferably in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended. Thecompounds and compositions of the present invention may, for example, beadministered orally, mucosally, topically, rectally, pulmonarily such asby inhalation spray, or , parentally including intravascularly,intravenously, intraperitoneally, subcutaneously, intramuscularlyintrasternally and infusion techniques, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers, adjuvants,and vehicles.

[0482] The pharmaceutically active compounds of this invention can beprocessed in accordance with conventional methods of pharmacy to producemedicinal agents for administration to patients, including humans andother mammals.

[0483] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units were tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,preferably from about 1 to 500 mg, more preferably from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods.

[0484] The amount of compounds which were administered and the dosageregimen for treating a disease condition with the compounds and/orcompositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, thetype of disease, the severity of the disease, the route and frequency ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. A daily dose of about 0.01 to 500 mg/kg body weight, preferablybetween about 0.5 and about 50 mg/kg body weight and most preferablybetween about 0.1 to 20 mg/kg body weight, may be appropriate may beappropriate. The daily dose can be administered in one to four doses perday.

[0485] For therapeutic purposes, the active compounds of this inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

[0486] In the case of psoriasis and other skin conditions, it may bepreferable to apply a topical preparation of compounds of this inventionto the affected area two to four times a day.

[0487] Formulations suitable for topical administration include liquidor semi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

[0488] When formulated in an ointment, the active ingredients may beemployed with either paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at Least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs.

[0489] The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

[0490] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

[0491] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[0492] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients were dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The active ingredients were preferably present insuch formulations in a concentration of 0.5 to 20%, advantageously 0.5to 10% and particularly about 1.5% w/w.

[0493] Formulations for parenteral administration may be in the form ofaqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules using one or more of the carriers ordiluents mentioned for use in the formulations for oral administrationor by using other suitable dispersing or wetting agents and suspendingagents.

[0494] The compounds may be dissolved in water, polyethylene glycol,propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesameoil, benzyl alcohol, sodium chloride, tragacanth gum, and/or variousbuffers. Other adjuvants and modes of administration are well and widelyknown in the pharmaceutical art. The active ingredient may also beadministered by injection as a composition with suitable carriersincluding saline, dextrose, or water, or with cyclodextrin (ie.Captisol), cosolvent solubilization (ie. propylene glycol) or micellarsolubilization (ie. Tween 80). The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed, including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0495] For pulmonary administration, the pharmaceutical composition maybe administered in the form of an aerosol or with an inhaler includingdry powder aerosol.

[0496] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable non-irritating excipientsuch as cocoa butter and polyethylene glycols that are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[0497] The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[0498] The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

[0499] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

[0500] All mentioned references, patents, applications and publications,are hereby incorporated by reference in their entirety, as if herewritten.

What is claimed is:
 1. A compound of the formula

wherein R¹ is independently selected from phenyl substituted with R^(4a)and optionally substituted with 1-4 R⁴, and heteroaryl substituted withR^(4a) and optionally substituted with 1-4 R⁴ on each ring; wherein R²is independently selected from H, halo, R³, R⁸, —NHR³, —NHR⁵, —NHR⁶,—NR⁵R⁵, —NR⁵R⁶, —SR⁵, —SR⁶, —SR³, —OR⁵, —OR⁶, O³, —C(O)R³, heterocyclyloptionally substituted with 1-4 independent R⁴ on each ring, and C₁-C₁₀alkyl optionally substituted with 1-4 independent R⁴; wherein R³ isindependently selected from phenyl optionally substituted with 1-3independent R⁴, and heteroaryl optionally substituted with 1-2independent R⁴; wherein R⁴ is independently selected from H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, aryl, R⁸, halo, SR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁵R¹⁶, COOR⁵,NO₂, CN, C(O)R⁵, C(O)C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)NR⁵R⁵,NR⁵C(O)C(O)R⁵, NR⁵C(O)R⁵, NR⁵ (COOR⁵), NR⁵C(O)R⁸, NR⁵S(O)_(n)NR⁵R⁵,NR⁵S(O)_(n)R⁵, NR⁵S(O)_(n)R⁸, NR⁵C(O)C(O)NR⁵R⁵, NR⁵C(O)C(O)NR⁵R⁶,OC(O)NR⁵R⁵, OS(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)OR⁵, P(O)(OR⁵)₂, C₁-C₁₀ alkylsubstituted with 1-3 substituents independently selected from aryl, R⁷and R⁸, and C₂-C₁₀ alkenyl substituted with 1-3 substituentssubstituents independently selected from aryl, R⁷ and wherein R^(4a) is—NR⁵R¹⁶ or CH₂NR⁵R¹⁶; wherein R⁵ is independently selected from H,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, aryl, R⁹, C₁-C₁₀ alkyl substituted with 1-3 substituentsindependently selected from aryl, R⁷ and R⁹; C₃-C₁₀ cycloalkylsubstituted with 1-3 substituents independently selected from aryl, R⁷or R⁹; and C₂-C₁₀ alkenyl substituted with 1-3 substituentsindependently selected from aryl, R⁷ and R⁹; wherein R^(5a) is aryl orR⁹; wherein R⁸ is independently selected from C(O)R⁵, COOR⁵, C(O)NR⁵R⁵,C(═NR⁵)NR⁵R⁵, and S(O)_(n)NR⁵; wherein R⁷ is independently selected fromhalo, CF₃, SR¹⁰, OR¹⁰, OC(O)R¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂,CN, C(O)R¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, N(R¹⁰) (COOR¹⁰),S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)R¹⁰, and P(O)(OR⁵)₂;wherein R⁸ is independently selected from 3-8 membered monocyclic, 7-12membered bicyclic, and 11-14 membered tricyclic ring system comprising1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms independently selected fromO, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2,3 or 4 atoms of each ring may be substituted by a substituentindependently selected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl, aryl, R⁹, halo, sulfo,oxo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁶R⁶, COOR⁵, NO₂, CN, C(O)R⁵,C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)NR⁵R⁵, NR⁵C(O)R⁹, NR⁵S(O)_(n)NR⁵R⁵,NR⁵S(O)_(n)R⁹, C₁-C₁₀ alkyl substituted with 1-3 substituentsindependently selected from R⁷, R⁹ or aryl; or C₂-C₁₀ alkenylsubstituted with 1-3 substituents independently selected from R⁷, R⁹ andaryl; wherein R^(8a) is independently selected from 3-8 memberedmonocyclic, 7-12 membered bicyclic, and 11-14 membered tricyclic ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatomsindependently selected from O, N, or S, which may be saturated orunsaturated, and wherein 0, 1, 2, 3 or 4 atoms of each ring may besubstituted by a substituent independently selected from C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl,aryl, R⁹, halo, Sulfo, oxo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁶R⁶,COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)NR⁵R⁵,NR⁵C(O)R⁹, NR⁵S(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)R⁹, C₁-C₁₀ alkyl substitutedwith 1-3 substituents independently selected from R⁷, R⁹ or aryl; orC₂-C₁₀ alkenyl substituted with 1-3 substituents independently selectedfrom R⁷, R⁹ or aryl; provided R^(1a) is substituted with C(O)NHR^(5a);wherein R⁹ is independently selected from 3-8 membered monocyclic, 7-12membered bicyclic, and 11-14 membered tricyclic ring system comprising1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms independently selected fromO, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2or 3 atoms of each ring may be substituted by a substituentindependently selected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C10alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl, halo, sulfo, oxo,haloalkyl, SR¹⁰, OR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN,C(O)R¹⁰, S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰; wherein R¹⁰ isindependently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₄-C10 cycloalkenyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkyloptionally substituted with 1-3 substituents independently selected fromC₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀) cycloalkenyl,halo, CF₃, OR¹², SR¹², NR¹²R¹², COOR¹², NO₂, CN, C(O)R¹², C(O)NR¹²R¹²,NR12C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹², and OC(O)R¹²; and phenyloptionally substituted with 1-3 substituents independently selected fromC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, halo, CF₃, OR¹², SR¹², NR¹²R¹², COOR¹², NO₂, CN, C(O)R¹²,C(O)NR¹²R¹², NR¹²C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹², and OC(O)R¹²;wherein R¹¹ is independently selected from C(O)R¹⁰, COOR¹⁰, C(O)NR¹⁰R¹⁰and S(O)_(n)R¹⁰; wherein R¹² is independently selected from H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, C₁-C₁₀ alkyl substituted with 1-3 substituentsindependently selected from C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₄-C₁₀ cycloalkenyl, halo, OR¹³, SR¹³, NR¹³R¹³, COOR¹³, NO₂,CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³, and OC(O)R¹³, and phenyloptionally substituted with 1-3 substituents independently selected fromC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, halo, OR¹³, SR¹³, NR¹³, R¹³, COOR¹³, NO₂, CN, C(O)R¹³,C(O)NR¹³R¹³, NR¹³C(O)R¹³, and OC(O)R¹³; wherein R¹³ is independentlyselected from H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₄-C₁₀ cycloalkenyl, C₁-C₁₀ alkyl optionally substitutedwith halo, OR¹⁴, SR¹⁴, NR¹⁴R¹⁴, COOR¹⁴, NO₂, and CN, and phenyloptionally substituted with halo, CF₃, OR¹⁴, SR¹⁴, NR¹⁴R¹⁴, COOR¹⁴, NO₂,and CN; wherein R¹⁴ is independently selected from H, C₁-C₁₀ alkyl,C₃-C₁₀ cycloalkyl and phenyl; wherein R¹⁶ is independently selected fromC₄-C₁₀ cycloalkenyl, aryl, and R^(8a); provided aryl is substituted withC(O)NHR^(5a); wherein n is independently 1 or 2; and wherein aryl isindependently a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbontricyclic aromatic ring system optionally substituted with 1-3substituents independently selected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkenyl, R⁹, halo,haloalkyl, CF₃, OR¹⁰, SR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰,C(O)C(O)R¹⁰, C(O)NR⁵R⁵, N(R¹⁰)C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰,N(R¹⁰O)S(O)_(n)R¹⁰, N(R¹⁰)(COOR¹⁰), NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)R⁹,NR¹⁰S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)R⁹, NR¹²C(O)C(O)NR¹²R¹², S(O)_(n)R¹⁰,S(O)_(n)NR¹⁰R¹⁰, OC(O)R¹⁰, C₁-C₁₀ alkyl substituted with 1-3substituents independently selected from R⁹, halo, CF₃, OR¹⁰, SR¹⁰,OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰,OC(O)NR¹⁰R¹⁰, C(O)NR⁵R⁵, N(R¹⁰)C(O)R¹⁰, N(R¹⁰) (COOR¹⁰),S(O)_(n)NR¹⁰R¹⁰; R¹⁰; and C₂-C₁₀ alkenyl substituted with 1-3substituents independently selected from R⁹, halo, CF₃, OR¹⁰, SR¹⁰),OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰,OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, N(R¹⁰)(COOR¹⁰) andS(O)_(n)NR¹⁰R¹⁰.
 2. Compound of claim 1 wherein R¹ is selected fromphenyl substituted with R^(4a) and optionally substituted with 1-3 R⁴,and 5-10 membered heteroaryl substituted with R^(4a) and optionallysubstituted with 1-3 R⁴; wherein R² is selected from halo, R³, R⁸,—NHR³, —NHR⁵, —NHR⁶, —NR⁵R⁵, —NR⁵R⁶, —SR⁵, —SR⁶, —SR³ ₁, —OR⁵, —OR⁶,—OR³, —C(O)R³, 4-10 membered heterocyclyl optionally substituted with1-4 independent R⁴, and C₁-C₄ alkyl optionally substituted with 1-3independent R⁴; wherein R³ is independently selected from phenyloptionally substituted with 1-5 independent R⁴, and heteroaryloptionally substituted with 1-4 independent R⁴; wherein R⁴ isindependently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, phenyl, R⁸, halo selectedfrom fluoro and chloro, SR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁵R¹⁶, COOR⁵, NO₂,CN, C(O)R⁵, C(O)C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)R⁵, S(O)_(n)NR⁵R⁵,NR⁵C(O)NR⁵, NR⁵C(O)C(O)R⁵, NR⁵C(O)R⁵, NR⁵(COOR⁵), NR⁵C(O)R⁸,NR⁵S(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)R⁵, NR⁵S(O)_(n)R⁸, NR⁵C(O)C(O)NR⁵R⁵,NR⁵C(O)C(O)NR⁵R⁶, OC(O)NR⁵R⁵, OS(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)OR⁵, C₁-C₆alkyl substituted with 1-3 substituents independently selected fromphenyl, R⁷ and R⁸; and C₂-C₆ alkenyl substituted with 1-3 substituentsindependently selected from phenyl, R⁷ or R⁸; wherein R^(4a) is —NR⁵R¹⁶;wherein R⁵ is independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, phenyl, R⁹, C₁-C₆alkyl substituted with 1-3 substituents independently selected fromphenyl, R⁷ and R⁹ groups, C₃-C₆ cycloalkyl substituted with 1-3substituents independently selected from phenyl, R⁷ and R⁹ groups, andC₂-C₆ alkenyl substituted with 1-3 substituents independently selectedfrom phenyl, R⁷ and R⁹; wherein R5a is phenyl or R^(9a); wherein R⁶ isindependently selected from C(O)R⁵, COOR⁵, C(O)NR⁵R⁵, C(═NR⁵)NR⁵R⁵ andS(O)_(n)R⁵; wherein R⁷ is independently selected from chloro, fluoro,CF₃, SR¹⁰, OR¹⁰, OC(O)R¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN,C(O)R ¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, N(R¹⁰))(COOR¹⁰),S(O)_(n)NR¹⁰R¹⁰, NR¹⁰OS(O)_(n)NR¹⁰R¹⁰ and NR¹⁰S(O)_(n)R¹⁰; wherein R⁸ isindependently a 3-8 membered monocyclic, or 7-12 membered bicyclic ringsystem comprising 1-3 heteroatoms if monocyclic, or 1-6 heteroatoms ifbicyclic, said heteroatoms independently selected from O, N, or S, whichmay be saturated or unsaturated, and wherein 0, 1, 2, 3 or 4 atoms ofeach ring may be substituted by substituents independently selected fromC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆cycloalkenyl, phenyl, R⁹, chloro, fluoro, oxo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵,NR⁵R⁶, NR⁶R⁶, COOR⁵, NO₂, CN, C(O)⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵,NR⁵C(O)NR⁵R⁵, NR⁵C(O)R⁹, NR⁵S(O)_(n)NR⁵R⁵ ₁, NR⁵S(O)_(n)R⁹, C₁-C₆ alkylsubstituted with 1-3 substituents independently selected from R⁷, R⁹ andphenyl, and C₂-C₆ alkenyl substituted with 1-3 substituentsindependently selected from R⁷, R⁹ and phenyl; wherein R^(8a) isindependently a 5-6 membered monocyclic, or 9-10 membered bicyclic ringsystem, comprising 1-3 heteroatoms if monocyclic, or 1-6 heteroatoms ifbicyclic, said heteroatoms independently selected from O, N, or S, whichmay be saturated or unsaturated, and wherein 0, 1, 2, 3 or 4 atoms ofeach ring may be substituted by substituents independently selected fromC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆cycloalkenyl, phenyl, R⁹, halo, oxo, SR5, OR OC(O)R⁵, NR⁵R⁵, NR⁵R⁶,NR⁶R⁶, COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁹,NR⁵S(O)_(n)NR⁹, C₁-C₆ alkyl substituted with 1-3 substituentsindependently selected from R⁷, R⁹ and phenyl, and C₂-C₆ alkenylsubstituted with 1-3 substituents independently selected from R⁷, R⁹ andphenyl, provided R^(8a) is substituted with C(O)NHR^(5a); wherein R⁹ isindependently a 3-8 membered monocyclic, or 7-12 membered bicyclic, ringsystem comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatomsindependently selected from O, N, or S, which may be saturated orunsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may besubstituted by a substituent independently selected from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, oxo, C₁-6 haloalkyl, SR¹⁰, OR¹⁰, NR¹⁰R¹⁰,NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, S(O)_(n)R¹⁰,S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰; wherein R^(9a) is independently a 5-6membered monocyclic, or 9-10 membered bicyclic ring system comprising1-3 heteroatoms if monocyclic, or 1-6 heteroatoms if bicyclic, saidheteroatoms independently selected from O, N, or S, which may besaturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ringmay be substituted by a substituent independently selected from C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆cycloalkenyl, halo, oxo, C₁₋₆ haloalkyl, SR¹⁰, OR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹,NR¹¹R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, S(O)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, andC(O)NR¹⁰R¹⁰; wherein R¹⁰ is independently selected from H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl,C₁-C₆ alkyl substituted with 1-3 substituents independently selectedfrom, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkenyl, halo, OR¹², SR¹², NR¹²R¹², COOR, NO₂, CN, C(O)R¹²,C(O)NR¹²R¹², NR¹²C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹², and OC(O)R¹²,and phenyl optionally substituted with 1-3 substituents independentlyselected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, halo, OR¹², SR¹², NR¹²R¹², COOR¹², NO₂,CN, C(O)R¹², C(O)NR¹²R¹², NR¹²C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹²,and OC(O)R¹²; wherein R¹¹ is independently selected from C(O)R¹⁰,COOR¹⁰, C(O)NR¹⁰R¹⁰ and S(O)_(n)R¹⁰; wherein R¹² is independentlyselected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkyl substitutedwith 1-3 substituents independently selected from C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, halo, OR¹³, NR¹³R¹³,COOR¹³, NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³, and OC(O)R¹³, andphenyl optionally substituted with 1-3 substituents independentlyselected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, OR¹³,NR¹³R¹³, COOR¹³, NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³, andOC(O)R¹³; wherein R¹³ is independently selected from H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₁-C₆ alkyl optionally substituted with halo, CF₃,OR¹⁴, NR¹⁴R¹⁴, COOR¹⁴, NO₂, and CN, and phenyl optionally substitutedwith halo, OR¹⁴, NR¹⁴R¹⁴, COOR¹⁴, NO₂, and CN; wherein R¹⁴ isindependently selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl and phenyl;wherein R¹⁶ is selected from phenyl and R^(8a); provided phenyl issubstituted with C(O)NHR^(5a); wherein n is independently 1 or 2;wherein phenyl is optionally substituted with 1-3 substituentsindependently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, R⁹, halo, CF₃, OR¹⁰, SR¹⁰,NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, C(O)C(O)R¹⁰, C(O)NR⁵R⁵,N(R¹⁰)C(O)NR¹⁰R¹⁰, N(R¹⁰O)C(O)R¹⁰, N(R¹⁰)S(O)_(n)R¹⁰, N(R¹⁰)(COOR¹⁰),NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)R⁹, NR¹⁰S(O)_(n)NR¹⁰R¹⁰, NR¹⁰S(O)_(n)R⁹,NR¹²C(O)C(O)NR¹²R¹², S(O)_(n)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, OC(O)R¹⁰, C₁-C₆ alkylsubstituted with 1-3 substituents independently selected from R⁹, halo,OR¹⁰, SR¹⁰, OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN,C(O)R¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR⁵R⁵, N(R¹⁰)C(O)R¹⁰, N(R¹⁰) (COOR¹⁰),S(O)_(n)NR¹⁰R¹⁰, and R¹⁰; and C₂-C₆ alkenyl substituted with 1-3substituents independently selected from R⁹, halo, CF₃, OR¹⁰, SR¹⁰,OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰,OC((O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, N(R¹⁰)(COOR¹⁰) andS(O)_(n)NR¹⁰R¹⁰.
 3. Compound of claim 2 wherein R¹ is selected fromphenyl ortho-substituted with R^(4a) and optionally substituted with R⁴;and 5-10 membered heteroaryl ortho substituted with R^(4a) andoptionally substituted with R⁴; wherein R² is selected from halo, —NHR³,—NHR⁵, —NHR⁶, —NR⁵R⁵, 6-10 membered heterocyclyl optionally substitutedwith 1-2 independent R⁴ , and C₁-C₂ alkyl optionally substituted with1-3 substituents independently selected from phenyl, R⁸, chloro, fluoro,OR⁵, OC(O)R⁵, NR⁵R⁵ and COOR⁵; wherein R³ is independently selected fromphenyl optionally substituted with R⁴, and 5-10 membered heteroaryloptionally substituted with R⁴; wherein R⁴ is independently selectedfrom H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl,phenyl, R⁸, chloro, fluoro, OR⁵, NR⁵R⁵, NR⁵R⁶, NR⁵R¹⁶, COOR⁵, NO₂, CN,C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁵, NR⁵ (COOR⁵),NR⁵C(O)R⁵, NR⁵S(O)_(n)R⁵, NR⁵S(O)_(n)R⁸, NR⁵S(O)_(n)OR⁵, C₁-C₄ alkylsubstituted with 1-3 substituents independently selected from phenyl, R⁷and R⁸; and C₂-C₄ alkenyl substituted with 1-3 substituentsindependently selected from phenyl, R⁷ and R⁸; wherein R^(4a) is—NR⁵R¹⁶; wherein R⁵ is independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, phenyl, R⁹, C₁-C₄ alkyl substituted with 1-3 substituentsindependently selected from aryl, R⁷ or R⁹ groups, and C₃-C₆ cycloalkylsubstituted with 1-3 substituents independently selected from aryl, R⁷or R⁹ groups; wherein R^(5a) is phenyl or R^(9a); wherein R⁶ isindependently selected from C(O)R⁵, COOR⁵, C(O)NR⁵R⁵, C(═NR⁵)NR⁵R⁵, andS(O)_(n)R⁵; wherein R⁷ is independently selected from chloro, fluoro,CF₃, SR¹⁰, OR¹⁰, OC(O)R¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰, NO₂, CN,C(O)R¹⁰, C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, S(O)_(n)NR¹⁰R¹⁰, andNR¹⁰S(O)_(n)R¹⁰; wherein R⁸ is independently a 3-8 membered monocyclic,7-12 membered bicyclic ring system comprising 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, said heteroatoms independentlyselected from O, N, or S, which may be saturated or unsaturated, andwherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by asubstituent independently selected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl,R⁹, phenyl, chloro, fluoro, oxo, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, NR⁶R⁶,COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁹,NR⁵S(O)_(n)R⁹, and C₁-C₄ alkyl substituted with 1-3 substituentsindependently selected from R⁷, R⁹ and phenyl; wherein R^(8a) isindependently a 5-6 membered monocyclic, or 9-10 membered bicyclic ringsystem, comprising 1-3 heteroatoms if monocyclic, or 1-6 heteroatoms ifbicyclic, said heteroatoms independently selected from 0, N, or S, whichmay be partially saturated or unsaturated, and wherein 0, 1, 2, 3 or 4atoms of each ring may be substituted by a substituent independentlyselected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl, R⁹, oxo, phenyl, chloro,fluoro, OR⁵, OC(O)R⁵, NR⁵R⁵, NR⁵R⁶, COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵,S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁹, NR⁵S(O)_(n)R⁹, and C₁- C₄ alkyl substitutedwith 1-3 substituents independently selected from R⁷, R⁹ and phenyl;provided R^(8a) is substituted with C(O)NHR^(5a); wherein R⁹ isindependently a 3-8 membered monocuclic, or 7-12 membered bicyclic, ringsystem comprising 1-3 heteroatoms if monocyclic, or 1-6 heteroatoms ifbicyclic, said heteroatoms independently selected from O, N, or S, whichmay be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of eachring may be substituted by a substituent independently selected fromC₁-C₄ alkyl, C₃-C₆ cycloalkyl, fluoro, chloro, oxo, C₁-C₄ haloalkyl,OR¹⁰, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, S(O)_(n)R¹⁰,S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰; wherein R^(9a) is independently a 3-8membered monocyclic, or 7-12 membered bicyclic ring system comprising1-3 heteroatoms if monocyclic, or 1-6 heteroatoms if bicyclic, saidheteroatoms independently selected from O, N, or S, which may besaturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ringmay be substituted by a substituent independently selected from C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆cycloalkenyl, oxo, chloro, fluoro, C₁-C₄ haloalkyl, SR¹⁰, OR¹⁰, NR¹⁰R¹⁰,NR¹⁰R¹¹, NR¹¹R¹¹, COOR¹⁰ , NO₂, CN, C(O)R¹⁰, S(O)_(n)R¹⁰,S(O)_(n)NR¹⁰R¹⁰, and C(O)NR¹⁰R¹⁰; wherein R¹⁰ is independently selectedfrom H, C₁-C₄ alknyl, C₃-C₆ cycloalkyl, C₁-C₄ alkyl optionallysubstituted with, 1-3 substituents independently selected from C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, OR¹², SR¹², NR¹²R¹², COOR¹²,chloro, fluoro, NO₂, CN, C(O)R¹², C(O)NR12R¹², NR¹²C(O)R¹²,S(O)_(n)NR¹²R¹², and OC(O)R¹²; and phenyl optionally substituted with1-3 substituents independently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl, OR¹², SR¹²,NR¹²R¹², COOR¹², NO₂, CN, C(O)R¹², C(O)NR^(12 R) ¹², chloro, fluoro,NR¹²C(O)R¹², N(R¹²)(COOR¹²), S(O)_(n)NR¹²R¹², and OC(O)R¹²; wherein R¹¹is independently selected from C(O)R¹⁰, COOR₁₀, C(O)NR¹⁰R¹⁰ andS(O)_(n)R¹⁰; wherein R¹² is independently selected from H, C₁-C₄ alkyl,C₃-C₆ cycloalkyl, C₁-C₄ alkyl substituted with 1-3 substituentsindependently selected from C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, OR¹³, fluoro, chloro, NR¹³R¹³, COOR¹³,NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³, and OC(O)R¹³, and phenyloptionally substituted with 1-3 substituents independently selected fromC₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, CF₃, OR¹³, NR¹³R¹³, COOR¹³,fluoro, chloro, NO₂, CN, C(O)R¹³, C(O)NR¹³R¹³, NR¹³C(O)R¹³ and OC(O)¹³;wherein R¹³ is independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkyl optionally substituted with OR¹⁴, NR¹⁴R¹⁴ andCOOR¹⁴, and phenyl optionally substituted with halo, CF₃, OR¹⁴, NR¹⁴R¹⁴₁, and COOR¹⁴; wherein R¹⁴ is independently selected from H, C₁-C₄alkyl, C₃-C₆ cycloalkyl and phenyl; wherein R¹⁶ is selected from phenyland R^(8a); provided phenyl is substituted with C(O)NHR^(5a); wherein nis 2; wherein phenyl is optionally substituted with 1-3 substituentsindependently selected from C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,C₃-C₆ cycloalkyl, R⁹, C₁-C₄, haloalkyl, fluoro, chloro, OR¹⁰, NR¹⁰R¹⁰,NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, C(O)NR⁵R⁵, N(R¹⁰)C(O)R¹⁰,N(R¹⁰)S(O)_(n)R¹⁰, NR¹⁰C(O)R⁹, NR¹⁰S(O)_(n)R⁹, S(O)_(n)R¹⁰,S(O)_(n)NR¹⁰R¹⁰, OC(O)R¹⁰, C₁-C₄ alkyl substituted with 1-3 substituentsindependently selected from R⁹, fluoro, chloro, OR¹⁰, SR¹⁰, OC(O)R¹⁰,NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN, C(O)R¹⁰, OC(O)NR¹⁰R¹⁰,C(O)NR⁵R⁵, N(R¹⁰)C(O)R¹⁰, and S(O)_(n)NR¹⁰R¹⁰; and C₂-C₄ alkenylsubstituted with 1-3 substituents independently selected from R⁹, halo,OR¹⁰, SR¹⁰, OC(O)R¹⁰, NR¹¹R¹¹, NR¹⁰R¹⁰, NR¹⁰R¹¹, COOR¹⁰, NO₂, CN,C(O)R¹⁰, OC(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹⁰, N(R¹⁰)C(O)R¹⁰, and S(O)_(n)NR¹⁰R¹⁰.4. Compound of claim 3 wherein R¹ is selected from phenyl orthosubstituted with R^(4a), and heteroaryl selected from isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, benzothienyl,benzofuryl, benzimidazolyl, benzoxazolyl, and benzthiazolyl, whereinheteroaryl is ortho-substituted with R^(4a); wherein R² is selected fromfluoro, chloro, bromo, —NHR⁵, and methyl optionally substituted withphenyl, R⁸, chloro, fluoro, OR⁵, OC(O)R⁵, NR⁵R⁵and COOR⁵; wherein R⁴ isindependently selected from C₁-C₄ alkyl, optionally substituted phenyl,chloro, fluoro, OR⁵, and C₁-C₄ alkyl substituted with 1-3 substituentsindependently selected from optionally substituted phenyl and R⁸;wherein R^(4a) is —NHR16 wherein R⁵ is independently selected from H,C₁-C₄ alkyl, C₃-C₄ cycloalkyl, optionally substituted phenyl, R⁹ , andC₁-C₃ alkyl substituted with 1-3 substituents independently selectedfrom optionally substituted phenyl, R⁷ and R⁹ groups, and wherein R^(5a)is selected from optionally substituted phenyl and R^(9a); wherein R⁶ isC(O)R⁵; wherein R⁷ is independently selected from chloro, fluoro, CF₃,OR¹⁰, NR¹⁰R¹⁰, COOR¹⁰, NO₂, CN, and C(O)R¹⁰; wherein R⁸ is 5-6 memberedheteroaryl optionally substituted with a substituent independentlyselected from C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl, optionally substitutedphenyl, R⁹, OR¹⁰, NR¹⁰R¹⁰, COOR¹⁰, C(O)R¹⁰, OC(O)R¹⁰, and C(O)NR¹⁰R¹⁰;wherein R^(8a) is independently a 5-6 membered heteroaryl, or 9-10membered heteroaryl comprising 1-2 heteroatoms if monocyclic, or 1-4heteroatoms if bicyclic, said heteroatoms independently selected from O,N, or S, and wherein 0, 1, or 2 atoms of each ring may be substituted bysubstituents independently selected from C₁-C₄ alkyl, optionallysubstituted phenyl, R⁹, chloro, fluoro, oxo, OR⁵, and C₁-C₄ alkylsubstituted with 1-3 substituents independently selected from R⁷, R⁹ andoptionally substituted phenyl; provided R^(8a) is substituted withC(O)NHR^(5a); wherein R⁹ is independently a 5-6 membered heteroaryl, or9-10 membered bicyclic heteroaryl, ring system comprising 1-2heteroatoms if monocyclic or 1-4 heteroatoms if bicyclic, saidheteroatoms independently selected from O, N, or S, and wherein 0, 1, or2 atoms of each ring may be substituted by a substituent independentlyselected from C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl, optionally substitutedphenyl, R⁸, OR¹⁰, NR¹⁰R¹⁰, COOR¹⁰, C(O)R¹⁰, OC(O)R¹⁰, and C(O)NR¹⁰R¹⁰;wherein R^(9a) is independently a 5-6 membered heteroaryl, or 9-10membered heteroaryl bicyclic ring system comprising 1-2 heteroatoms ifmonocyclic, or 1-3 heteroatoms if bicyclic, said heteroatomsindependently selected O, N, or S, and wherein 0, 1, or 2 atoms of eachring may be substituted by a substituent independently selected fromC₁-C₃ alkyl, halo, oxo, C₁-C₃ haloalkyl and OR¹⁰; wherein R¹⁰ isindependently selected from H, methyl and C₁-C₃ alkyl substituted with1-3 substituents independently selected from fluoro, chloro, hydroxy,methoxy, optionally substituted phenyl and R⁹, and optionallysubstituted phenyl; and wherein R¹⁶ is selected from phenyl and R^(8a);provided phenyl is substituted with C(O)NHR^(5a); wherein optionallysubstituted phenyl is unsubstituted or substituted with 1-3 substituentsindependently selected from C₁-C₃ alkyl, R⁹, fluoro, chloro, C₁-C₃haloalkyl, OR¹⁰, NR¹⁰R¹⁰, COOR¹⁰, C(O)R¹⁰, C(O)NR⁵R⁵, OC(O)R¹⁰, andC₁-C₃ alkyl substituted with 1-2 substituents independently selectedfrom phenyl and R⁹; and pharmaceutically acceptable salts thereof. 5.Compound of claim 1 and pharmaceutically acceptable salts thereofselected from:N-(4-phenoxyphenyl)-3-{1-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-benzimidazo-1-2-ylamino}benzamide;N-(4-chlorophenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzamide;N-(phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide;N-(4-phenoxy-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}-benzamide;3-[3-(4-amino-[1,3,5]triazin-2-yl)-pyridin-2-ylamino]-N-(4-phenoxy-phenyl)benzamide;and3-[3-(4-amino-[1,3,5]triazin-2-yl)-pyridin-2-ylamino]-N-(3-isopropyl-phenyl)-benzamide.6. A compound of claim 1 wherein R¹ is

wherein R^(1a) is selected from unsubstituted or substituted aryl,5-6-membered heteroaryl and 9-10 membered fused heteroaryl, whereinR^(1a) is substituted with one or more substituents independentlyselected from halo, C₁-₆-alkyl, optionally substituted C₃-₆-cycloalkyl,optionally substituted phenyl, C₁-₆-haloalkoxy, optionally substitutedphenyloxy, benzyl, optionally substituted 5-6 memberedheterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl,optionally substituted heteroaryloxy, C₁-₆-haloalkyl, and C₁-₆-alkoxy;wherein R²is selected from fluoro, chloro, bromo, NHR⁵ and methyloptionally substituted with 1 to 3 substituents independently selectedfrom phenyl, R⁹, chloro, fluoro, OR⁵, OC(O)R⁵, NR⁵R⁵and COOR⁵; whereinR⁴ is selected from C₁-C₄ alkyl, optionally substituted phenyl, chloro,fluoro, hydroxy, methoxy and benzyl; wherein R⁵ is independentlyselected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, R⁹, phenyl optionally substituted withR⁴, and C₁-C₄ alkyl substituted with 1-3 substituents independentlyselected from aryl, R⁷ and R⁹ groups; and wherein R⁹ is selected from5-6-membered heteroaryl, and wherein 0, 1, 2 or 3 atoms of each ring maybe substituted by a substituent independently selected from C₁-C₄ alkyl,fluoro, chloro, trifluoromethyl, optionally substituted phenyl, hydroxy,methoxy, amino, methylamino, carboxy, methoxycarbonyl, formyl,methylcarbonyl, acetyl, and aminocarbonyl; and pharmaceuticallyacceptable salts thereof.
 7. A compound of claim 6 wherein R^(1a) isselected from phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl,quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl,benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, andbenzthiazolyl; wherein R^(1a) is substituted with one or moresubstituents independently selected from chloro, fluoro, amino, hydroxy,cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl,isobutyl, methylpiperazinylmethyl, trifluoromethyl, phenyloxy, methoxyand ethoxy; wherein R² is selected from —NHR⁵, fluoro, chloro, bromo,benzyl, trifluoromethyl, hydroxymethyl, methoxymethyl, aminomethyl andmethyl; and wherein R⁵ is independently selected from H, methyl andphenyl optionally substituted with chloro, fluoro, hydroxy, and methoxy;and pharmaceutically acceptable salts thereof.
 8. A compound of FormulaII

wherein A¹, A² and A³ are independently selected from C, CH, O, S, N andNH; wherein ring Z is selected from 5- or 6-membered heteroaryl andphenyl; wherein X^(a) is selected from

wherein Z^(a) is oxygen or sulfur; wherein R^(z) is C₁-C₄ alkylenyl,where one of the CH₂ groups may be substituted with O or an —NH—;wherein R^(1a) is selected from a) substituted or unsubstituted 6-10membered aryl, b) substituted or unsubstituted 5-6 memberedheterocyclyl, c) substituted or unsubstituted 9-10 membered fusedheterocyclyl, d) cycloalkyl, and e) cycloalkenyl; wherein R^(1a) isoptionally substituted with one or more substituents independentlyselected from halo, —OR¹⁵, —SR¹⁵, —CO₂R¹⁵, —CONR¹⁵R¹⁵, —COR¹⁵, —NR¹⁵R¹⁵,—NH(C₁-C₄ alkylenylR¹⁵), —SO₂R¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵C(O)OR⁵,—NR¹⁵C(O)R¹⁵, optionally substituted cycloalkyl, optionally substituted5-6 membered heterocyclyl, optionally substituted phenyl, lower alkylsubstituted with R⁴, cyano, nitro, lower alkenyl and lower alkynyl;wherein R⁴ and R^(4b) are independently selected from H, C₁-C₃ alkyl,C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl,phenyl, 5-6 membered heterocyclyl, halo, CF₃, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵,COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, S(O)_(n)R⁵, S(O)_(n)NR⁵R⁵, NR⁵C(O)R⁵,NR⁵(COOR⁵), NR⁵S(O)_(n)R⁵, OC(O)NR⁵R⁵, OS(O)_(n)NR⁵R⁵, NR⁵S(O)_(n)OR⁵,C₁-C₆ alkyl substituted with 1-3 substituents independently selectedfrom optionally substituted phenyl and optionally substituted 5-6membered heterocyclyl, and C₂-C₆ alkenyl substituted with 1-3substituents independently selected from optionally substituted phenyland optionally substituted 5-6 membered heterocyclyl; wherein R⁵ isselected from HI lower alkyl, phenyl and lower aralkyl; wherein R^(5b)is independently selected from H, C₁-C₄ alkyl, phenyl optionallysubstituted with R⁴, and C₁-C₄ alkyl substituted with 1-3 substituentsindependently selected from R⁴; and wherein R¹⁵ is selected from H,lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆ cycloalkyl, andlower haloalkyl; and wherein n is 0, 1 or 2; and pharmaceuticallyacceptable salts thereof.
 9. Compound of claim 8 wherein Z is 5-memberedheteroaryl selected from thienyl, furanyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl;wherein X^(a) is selected from

wherein R^(z) is C₁-C₂ alkylenyl, where one of the CH₂ groups may besubstituted with O or —NH—; wherein R^(1a) is selected from phenyl,naphthyl, indenyl, tetrahydronaphthyl, 5-6 membered heteroaryl, and 9-10membered fused heteroaryl; wherein R^(1a) is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, —OR¹⁵, —SR¹⁵, —SO₂R¹⁵, —CO₂R¹⁵, —CONR¹⁵R¹⁵, —COR¹⁵, —NR¹⁵R¹⁵,—NH(C₁-C₂ alkylenylR¹⁵), —(C₁-C₂ alkylenyl)NR¹⁵R¹⁵, —SO₂NR¹⁵R¹⁵,—NR¹⁵C(O)OR¹⁵, —NR¹⁵C(O)R¹⁵, optionally substituted cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, optionally substituted phenyl-C₁₋₂-alkylenyl, optionallysubstituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, C₁₋₄-alkyl,cyano, C₁₋₄-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R⁴ isselected from H, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₃-C₆ cycloalkyl, phenyl,5-6 membered heteroaryl, fluoro, chloro, CF₃, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵,COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, SO₂R⁵, SO₂NR⁵R⁵, NR⁵SO₂R⁵, and C₁-C₆alkyl substituted with 1-3 substituents independently selected fromoptionally substituted phenyl and optionally substituted 5-6 memberedheteroaryl; wherein R^(4b) is H; wherein R⁵ is selected from H, methyland ethyl; wherein R^(5b) is independently selected from H, C₁-C₂ alkyl,phenyl optionally substituted with R⁴, and methyl substituted with 1-3substituents independently selected from phenyl, fluoro, chloro, CF₃,methoxy, acetyl, amino, methoxycarbonyl; and wherein R¹⁵ is selectedfrom H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl, and C₁₋₂-haloalkyl; andpharmaceutically acceptable salts thereof.
 10. Compound of claim 9wherein Z is selected from

wherein X^(a) is wherein R^(1a) is selected from phenyl, thienyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl,thiazolyl, thiadiazolyl, furyl, pyrrolyl, indazolyl, indolyl,2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl,benzodioxanyl, and quinazolinyl; wherein R^(1a) is unsubstituted orsubstituted with one or more substituents selected from chloro, fluoro,bromo, methoxy, phenyloxy, benzyl, methylthio, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,difluoromethyl, pentafluoroethyl, hydroxymethyl, cyano, carboxy,aminocarbonyl, methylcarbonyl, amino, methylamino, cyclopropyl,cyclohexyl, piperidinyl, morpholinyl, N-methylpiperazinyl,N-ethylpiperazinyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, methylaminothiocarbonyl,N-methylamino-methylenyl, optionally substituted phenyl,N,N-diethylamino, and N,N-dimethylamino; wherein R⁴ is selected from H,methyl, phenyl, fluoro, chloro, CF₃, methoxy, methoxymethyl, acetyl,amino, methoxycarbonyl and benzyl; and wherein R^(5b) is H or methyl;and pharmaceutically acceptable salts thereof.
 11. Compound of claim 8wherein Z is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,and triazinyl; wherein X^(a) is selected from

wherein R^(z) is C₁-C₂ alkylenyl, where one of the CH₂ groups may besubstituted with O or —NH—; wherein R^(1a) is selected from phenyl,naphthyl, indenyl, tetrahydronaphthyl, 5-6 membered heteroaryl, and 9-10membered fused heteroaryl; wherein R^(1a) is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, —OR¹⁵, —SR¹⁵, —SO₂R¹⁵, CO₂R¹⁵, —CONR¹⁵R¹⁵, —COR¹⁵, —NR¹⁵R¹⁵,—NH(C₁-C₂ alkylenylR¹⁵), —(C₁-C₂ alkylenyl)NR¹⁵R¹⁵, —SO₂NR¹⁵R¹⁵,—NR¹⁵C(O)OR¹⁵, —NR¹⁵C(O)R¹⁵, optionally substituted cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, optionally substituted phenyl-C₁₋₂-alkylenyl, optionallysubstituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, C₁₄-alkyl, cyano,C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R⁴ is selected fromH, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₃-C₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, fluoro, chloro, CF₃, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵, COOR⁵, NO₂,CN, —C(O)R⁵, C(O)NR⁵R⁵, SO₂R⁵, SO₂NR⁵R⁵, NR⁵SO₂R⁵, and C₁-C₆ alkylsubstituted with 1-3 substituents independently selected from optionallysubstituted phenyl and optionally substituted 5-6 membered heteroaryl;wherein R^(4b) is H; wherein R⁵ is selected from H, methyl and ethyl;wherein R^(5b) is independently selected from H, C₁-C₂ alkyl, phenyloptionally substituted with R⁴, and methyl substituted with 1-3substituents independently selected from phenyl, fluoro, chloro, CF₃,methoxy, acetyl, amino, methoxycarbonyl; and wherein R¹⁵ is selectedfrom C₁-₂-alkyl, phenyl, C₃-C₆ cycloalkyl, and C₁₋₂-haloalkyl; andpharmaceutically acceptable salts thereof.
 12. Compound of claim 11wherein Z is selected from

wherein X^(a) is wherein R^(1a) is selected from phenyl, thienyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl,thiazolyl, thiadiazolyl, furyl, pyrrolyl, indazolyl, indolyl,2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl,benzodioxanyl, and quinazolinyl; wherein R^(1a) is unsubstituted orsubstituted with one or more substituents selected from chloro, fluoro,bromo, methoxy, phenyloxy, benzyl, methylthio, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,difluoromethyl, pentafluoroethyl, hydroxymethyl, cyano, carboxy,aminocarbonyl, methylcarbonyl, amino, methylamino, cyclopropyl,cyclohexyl, piperidinyl, morpholinyl, N-methylpiperazinyl,N-ethylpiperazinyl, morpholinylmethyl, methylpiperdinylmethyl,methylpiperazinylmethyl, methylaminothiocarbonyl,N-methylamino-methylenyl, optionally substituted phenyl,N,N-diethylamino, and N,N-dimethylamino; wherein R¹⁵ is selected from H,methyl, phenyl, cyclopropyl, cyclohexyl, and trifluoromethyl; wherein R⁴is selected from H, methyl, phenyl, fluoro, chloro, CF₃, methoxy,methoxymethyl, acetyl, amino, methoxycarbonyl and benzyl; and whereinR^(5b) is H, or methyl; and pharmaceutically acceptable salts thereof.13. Compound of claim 8 wherein Z is phenyl; wherein X^(a) is selectedfrom

wherein R^(z) is C₁-C₂ alkylenyl, where one of the CH₂ groups may besubstituted with O or —NH—; wherein R^(1a) is selected from phenyl,naphthyl, indenyl, tetrahydronaphthyl, 5-6 membered heteroaryl, and 9-10membered fused heteroaryl; wherein R^(1a) is unsubstituted orsubstituted with one or more substituents independently selected fromhalo, —OR , —SR¹⁵, SO₂R¹⁵, —CO₂R¹⁵, —CONR¹⁵R¹⁵, —COR¹⁵, —NR¹⁵R¹⁵,—NH(C₁-C₂ alkylenylR¹⁵), —(C₁-C₂ alkylenyl)NR¹⁵R^(15, —S)) ₂NR¹⁵R¹⁵,—NR¹⁵C(O)OR¹⁵, —NR¹⁵C(O)R¹⁵, optionally substituted cycloalkyl,optionally substituted 5-6 membered heterocyclyl, optionally substitutedphenyl, optionally substituted phenyl-C₁-₂-alkylenyl, optionallysubstituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, C₁₋₄-alkyl,cyano, C₁₋₂-hydroxyalkyl, nitro and C₁₋₂-haloalkyl; wherein R⁴ isselected from H, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₃-C₆ cycloalkyl, phenyl,5-6 membered heteroaryl, fluoro, chloro, CF₃, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵,COOR⁵, NO₂, CN, C(O)R⁵, C(O)NR⁵R⁵, SO₂R⁵, SO₂NR⁵R⁵, NR⁵SO₂R⁵, and C₁-C₆alkyl substituted with 1-3 substituents independently selected fromoptionally substituted phenyl and optionally substituted 5-6 memberedheteroaryl; wherein R^(4b) is H; wherein R⁵ is selected from H, methyland ethyl; and wherein R^(5b) is independently selected from H, C₁-C₂alkyl, phenyl optionally substituted with R⁴, and methyl substitutedwith 1-3 substituents independently selected from phenyl, fluoro,chloro, CF₃, methoxy, acetyl, amino, methoxycarbonyl; and wherein R¹⁵ isselected from H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl, andC₁₋₂-haloalkyl; and pharmaceutically acceptable salts thereof. 14.Compound of claim 13 wherein Z is;

wherein X^(a) is

wherein R^(1a) is selected from phenyl, thienyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl,furyl, pyrrolyl, indazolyl, indolyl, 2,1,3-benzothiadiazolyl,isoquinolyl, quinolyl, tetrahydroquinolyl, benzodioxanyl, andquinazolinyl; wherein R^(1a) is unsubstituted or substituted with one ormore substituents selected from chloro, fluoro, bromo, methoxy,phenyloxy, benzyl, methylthio, methyl, ethyl, propyl, butyl, isopropyl,isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, hydroxymethyl, cyano, carboxy, aminocarbonyl,methylcarbonyl, amino, methylamino, cyclopropyl, cyclohexyl,piperidinyl, morpholinyl, N-methylpiperazinyl, N-ethylpiperazinyl,morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl,methylaminothiocarbonyl, N-methylamino-methylenyl, optionallysubstituted phenyl, N,N-diethylamino, and N,N-dimethylamino; whereinR^(1a) is selected from H, methyl, phenyl, cyclopropyl, cyclohexyl, andtrifluoromethyl; wherein R⁴ is selected from H, methyl, phenyl, fluoro,chloro, CF₃, methoxy, methoxymethyl, acetyl, amino, methoxycarbonyl andbenzyl; and wherein R^(5b) is H or methyl; and pharmaceuticallyacceptable salts thereof.
 15. A pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound of claim
 1. 16. Amethod of treating cancer in a subject, said method comprisingadministering an effective amount of a compound of claim
 1. 17. A methodof treating angiogenesis in a subject, said method comprisingadministering an effective amount of a compound of claim
 1. 18. A methodof treating KDR-related disorders in a mammal, said method comprisingadministering an effective amount of a compound of claim
 1. 19. A methodof treating proliferative disorders in a mammal, said method comprisingadministering an effective amount of a compound of claim 1.